ES2751741T3 - Procedure for making compounds useful as ATR kinase inhibitors - Google Patents

Abstract

A process for preparing a compound of formula I-2: ** Formula ** or a salt thereof, comprising the step of reacting a compound of formula 4-iv: ** Formula ** with a compound of the following structure : ** Formula ** under suitable coupling conditions to form a compound of formula 5-i: ** Formula ** and deprotect the compound of formula 5-i under suitable Boc deprotection conditions, in which the coupling conditions Suitable crossovers comprise combining a suitable palladium catalyst with a suitable base in a suitable solvent, and wherein the suitable palladium catalyst is selected from Pd [P (tBu) 3] 2, Pd (dtbpf) Cl2, Pd (PPh3) 2Cl2, Pd (PCy3) 2Cl2, Pd (dppf) Cl2 and Pd (dppe) Cl2; the suitable solvent is selected from one or more of the following: toluene, MeCN, water, EtOH, IPA, 2-Me-THF or IPAc; and the suitable base is selected from K2CO3, Na2CO3 or K3PO4.

Description

DESCRIPTION

Procedure for making compounds useful as ATR kinase inhibitors

Background of the Invention

ATR kinase (short for ATM and Rad3 related: ATM and Rad3 related ) is a protein kinase involved in cellular responses to DNA damage. The ATR kinase acts ATM kinase ( "ataxia telangiectasia mutated") and many other proteins to regulate the response of cells to damage DNA, commonly referred to as response to damage DNA ( "DDR" form siglada DNA Damage Response ). DDR stimulates DNA repair, promotes survival, and stops cell cycle progression by activating cell cycle checkpoints, providing time for repair. Without DDR, cells are much more sensitive to DNA damage and easily die from DNA damage induced by endogenous cellular processes, such as DNA replication or exogenous DNA damaging agents, commonly used in cancer treatment. .

Healthy cells can rely on a wide variety of different proteins for DNA repair, including DDR kinase ATR. In some cases, these proteins can offset each other by activating functionally redundant DNA repair processes. Conversely, many cancer cells carry defects in some of their DNA repair processes, such as ATM signaling, and therefore have increased dependence on their DNA repair proteins that remain intact, including to ATR.

Furthermore, many cancer cells either express activated oncogenes or lack key tumor suppressors, and this can make these cancer cells prone to dysregulated stages of DNA replication, which in turn results in DNA damage. ATR has been implicated as a critical component of DDR in response to altered DNA replication. As a result, these cancer cells are more dependent on a-Tr activity for the survival of healthy cells. Accordingly, ATR inhibitors may be useful for cancer treatment, used either alone or in combination with DNA damaging agents, as they suppress a DNA repair mechanism that is most important to cell survival in many cancer cells than normal healthy cells.

In fact, altered ATR function (eg, by gene deletion) has been shown to promote cancer cell death both in the absence and in the presence of DNA damaging agents. This suggests that ATR inhibitors may be effective as single agents and as potent sensitizers to radiation therapy or genotoxic chemotherapy.

For all these reasons, there is a need to develop potent and selective ATR inhibitors for the treatment of cancer, either as single agents or as combination therapies with radiation therapy or genotoxic chemotherapy. Additionally, it would be desirable to have a synthetic pathway for ATR inhibitors that is susceptible to large-scale synthesis and improves on currently known methods.

The ATR peptide can be expressed and isolated using a variety of methods known in the literature (see, for example, Unsal-Kapmaz et al., PNAS 99: 10, p. 6673-6678, Tuesday May 14, 2002; see also Kumagai et al Cell 124, p 943-955, March 10, 2006; Unsal-Kacmaz et al. Molecular and Cellular Biology, Feb 2004, p 1292-1300; and Hall-Jackson et al Oncogene 1999, 18, 6707-6713). WO 2010/071837 refers to pyrazine derivatives useful as ATR inhibitors.

Description of the figures

FIGURE 1a: XRPD free base of Compound I-2

FIGURE 2a: Free base TGA of Compound I-2

FIGURE 3a: Free base DSC of Compound I-2

FIGURE 4a: ORTEP representation of the asymmetric unit of the free-form single crystal structure of Compound I-2

FIGURE 1b: XRPD Compound I-2 • HCl

FIGURE 2b: TGA Compound I-2 • HCl

FIGURE 3b: DSC Compound I-2 • HCl

FIGURE 4b: ORTEP representation of the symmetric unit of the anhydrous structure of Compound I-2 • HCl.

FIGURE 1c: XRPD Compound I-2 • 2HCl

FIGURE 2c: TGA Compound I-2 • 2HCl

FIGURE 3c: DSC Compound I-2 • 2HCl

FIGURE 1d: XRPD Compound I-2 • HCl monohydrate

FIGURE 2d: TGA Compound I-2 • HCl Monohydrate

FIGURE 3d: DSC Compound I-2 • HCl monohydrate

FIGURE 1e: XRPD Compound I-2 • HCl • ² H ² O

FIGURE 2e: TGA Compound I-2 • HCl • ² H ² O

FIGURE 3e: DSC Compound I-2 • HCl • ² H ² O

FIGURE 4a: Free base solid state of Compound I-1

FIGURE 4b: Solid State 13 CNMR of Compound I-1 • HCl

Summary of the invention

The present invention relates to a process for the preparation of a compound of formula I-2 as defined in claim 1, with preferred embodiments set out in the dependent claims. The present disclosure relates to methods and intermediates for the preparation of compounds useful as ATR kinase inhibitors, such as aminopyrazine isoxazole derivatives and related molecules. Aminopyrazine-isoxazole derivatives are useful as ATR inhibitors and are also useful for preparing ATR inhibitors. The present disclosure also relates to solid forms of ATR inhibitors, as well as deuterated ATR inhibitors.

One aspect of the disclosure provides a process for preparing a compound of formula I:

which comprises preparing a compound of formula 4 :

from a compound of formula 3 :

under suitable oxime formation conditions.

Another aspect comprises preparing a compound of formula 4:

from a compound of formula 3 :

under suitable oxime formation conditions.

Another aspect of the present disclosure comprises a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein each R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R9a, R9b, R10, R11, R12 and R13 is independently hydrogen or deuterium, and at least one of R1a, R1b, R1c, R2, R3a,

R3b, R3c, R4, R5, R6, R7, R8, R9a, R9b, R10, R11, R12, and R13 is deuterium.

Yet another aspect of the disclosure provides solid forms of a compound of formula I-2 :

Other aspects of the invention are set out herein.

The present invention has several advantages over previously known methods. Firstly, the present process has fewer total synthetic steps compared to previously disclosed processes. Second, the present process has improved yields over the previously disclosed processes. Third, the present process is effective for compounds in which R3 is a wide range of groups, such as alkyl groups or a large, hindered moiety, such as a ring. Fourth, the present process comprises intermediates that are more stable and have a longer half-life. In certain embodiments, the Non-acidic formation of the oxime group in the present process allows the conservation of acid-sensitive protecting groups, such as Boc or CBz during the course of synthesis. In other embodiments, the process is easier to scale to larger amounts due to removal of chromatography as a purification step.

Detailed description of the invention

One aspect of the disclosure provides a process for preparing a compound for preparing a compound of formula 4 :

from a compound of formula 3 :

under suitable oxime formation conditions;

in which

R ¹ is Cia alkyl;

R ² is Ci-a alkyl;

or R ¹ and R2, together with the oxygen atoms to which they are attached, form an optionally substituted 5- or ^6- membered saturated heterocyclic ring having two oxygen atoms;

R ³ is hydrogen, Ci-a-alkyl or a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; wherein the heterocyclyl is optionally substituted with ^one occurrence of halo or C ¹ alkyl - ^3;

J ¹ is halo, C ^1-4 alkyl or alkoxy C ^{1 to 4;}

PG is a carbamate protecting group.

Another aspect provides a process for preparing a compound of formula I:

which includes the stages of:

prepare a compound of formula 4:

under suitable oxime formation conditions;

in which

R ¹ is Cia alkyl;

R ² is Ci-a alkyl;

or R ¹ and R2, together with the oxygen atoms to which they are attached, form an optionally substituted 5- or ^6- membered saturated heterocyclic ring having two oxygen atoms;

R ³ is hydrogen, C ¹ -alkyl or a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; wherein the heterocyclyl is optionally substituted with ^one occurrence of halo or C ¹ alkyl - ^3;

Q is phenyl, pyridyl, or an N-alkylated pyridine;

J ¹ is H, halo, C ^1-4 alkoxy or C ^1-4;

J ² is halo; CN; phenyl; oxazolyl; or a C ¹ -a aliphatic group in which up to 2 methylene units are optionally replaced by O, NR ", C (O), S, S (O) or S (O) ² ; said C ¹ -a aliphatic group it is optionally substituted with 1-3 fluorine or CN;

q is ⁰ , ¹ or ² ;

PG is a carbamate protecting group.

Another embodiment further comprises the step of protecting a compound of formula 2 :

under suitable protection conditions to form the compound of formula 3 .

Another embodiment further comprises the step of reacting a compound of formula 1:

to

with a suitable amine under suitable reductive amination conditions to form a compound of formula 2 .

In some embodiments, the suitable amine is NHCH ³ . In other embodiments, the suitable amine is O > - NH,

Another embodiment further comprises the step of reacting a compound of formula 4 :

under suitable isoxazole-forming conditions to form a compound of formula 5 :

Another embodiment further comprises the step of reacting a compound of formula 5 under suitable coupling conditions, followed by suitable deprotection conditions to form a compound of formula I.

In some embodiments, PG is Boc or Cbz. In some embodiments, PG is Boc.

In other embodiments, R1 is ethyl and R2 is ethyl.

In still other embodiments,

que Q es fenilo. En algunas realizaciones, Q está sustituido en la posición para con J², en el que q es 1.In some embodiments,

that Q is phenyl. In some embodiments, Q is substituted at the para position with J ² , where q is 1.

In some embodiments, J1 is H or halo. In some embodiments, J1 is H. In other embodiments, J1 is halo. In other embodiments, J2 is a C ^1-6 aliphatic group in which up to 1 methylene unit is optionally replaced by S (O) 2. In some embodiments, J2 is -S (O) 2- (C1-5 alkyl). In some embodiments, q is 1. According to another embodiment,

R ¹ is ethyl;

R ² is ethyl;

en el que Q es fenilo; J² es -S(⁰ )²-CH(CH³)²;

where Q is phenyl; J ² is -S ( ⁰ ) ² -CH (CH ³ ) ² ;

q is ¹ ;

In some embodiments, R ³ is ^{CH 3.} In some embodiments, R ³ is ^{CH 3.} In still other embodiments, R ³ is ^{CH 3} or

According to another embodiment, R ¹ is ethyl;

R ² is ethyl;

In some embodiments,

Reaction conditions

In some embodiments, suitable oxime formation conditions consist of a single stage sequence or a two stage sequence.

In some embodiments, the two-step sequence consists of first deprotecting the ketal group on the compound of formula 3 in an aldehyde under suitable deprotection conditions, and then forming the oxime of formula 4 under suitable oxime formation conditions. In some embodiments, suitable deprotection conditions comprise adding catalytic amounts of para-toluenesulfonic acid (pTSA), acetone, and water; and suitable oxime formation conditions comprise mixing together hydroxylamine, an amount acid catalytic, a dehydrating agent and an alcoholic solvent. In other embodiments, the acid is pTSA or HCl, the dehydration agent is molecular sieves or dimethoxyacetone, and the alcoholic solvent is methanol or ethanol.

In other embodiments, the single-step sequence comprises adding NH ² OH.HCl and a mixture of THF and water. In other embodiments, the sequence comprises adding N ^ O H.HCl with a mixture of 2-methyl tetrahydrofuran and water optionally buffered with Na ² SO ⁴ . In some embodiments, 1 equivalent of the compound of formula 3 is combined with 1.1 equivalents of NH ² OH.HCl in a 10: 1 v / v mixture of THF and water. In some embodiments, 1 equivalent of the compound of formula 3 is combined with 1.1 equivalents of N ^ OH.HCl in a 10: 1 v / v mixture of 2-methyl tetrahydrofuran and optionally Na ² SO ⁴ buffered water.

In other embodiments, the protection conditions are selected from the group consisting of

• R-OCOCl, a suitable tertiary amine base and a suitable solvent; wherein R is C ^1-6 alkyl optionally substituted with phenyl;

• R (CO ² ) OR ', a suitable solvent and optionally a catalytic amount of base, wherein R and R' are each independently C ^1-6 alkyl optionally substituted with phenyl;

• [RO (C = O)] ² O, a suitable base and a suitable solvent.

In some embodiments, the suitable base is ^Et3N, diisopropylamine and pyridine; and the suitable solvent is selected from a chlorinated solvent, an ether or an aromatic hydrocarbon. In other embodiments, the suitable base is ^Et3N, the suitable solvent is a chlorinated solvent selected between DCM. In still other embodiments, the protection conditions comprise adding 1.20 equivalents of (Boc) ² O and 1.02 equivalents of Et ³ N in DCM.

According to another suitable embodiment, the coupling conditions comprise adding a suitable metal and a suitable base in a suitable solvent. In other embodiments, the suitable metal is Pd [P (tBu) ³ ] ² ; the suitable solvent is a mixture of acetonitrile and water; and the suitable base is sodium carbonate. In still other embodiments, suitable coupling conditions comprise adding 0.1 equivalents of Pd [P (tBu) ³ ] ² ; 1 equivalent of boronic acid or ester; and 2 equivalents of sodium carbonate in a 2: 1 v / v ratio of acetonitrile / water at 60-70 ° C.

According to another embodiment, suitable deprotection conditions comprise combining the compound of formula 5 with a suitable acid in a suitable solvent. In some embodiments, the suitable acid is selected from para-toluenesulfonic acid (pTSA), HCl, TBAF, H ³ PO ⁴ or TFA and the suitable solvent is selected from acetone, methanol, ethanol, CH ² O ² , EtOAc, THF, 2-MeTHF, dioxane, toluene, or diethyl ether.

According to another embodiment, the suitable isoxazole-forming conditions consist of two steps, the first step comprising reacting the compound of formula 4 under suitable chloro-oxime formation conditions to form a chloro-oxime intermediate; the second step comprising reacting the chloroxime intermediate with acetylene under suitable cycloaddition conditions to form a compound of formula 5.

According to another embodiment, suitable chloroxime formation conditions are selected from

■ N-chlorosuccinimide and a suitable solvent or

■ potassium peroxymonosulfate, HCl and dioxane.

In some embodiments, the suitable solvent is selected from a non-protic solvent, an aromatic hydrocarbon, or an alkyl acetate. According to another embodiment, the suitable chloroxime formation conditions are 1.05 equivalents of N-chlorosuccinimide in isopropyl acetate at 40-50 ° C.

According to another embodiment, the suitable cycloaddition conditions consist of a suitable base and a suitable solvent. In some embodiments, the suitable base is selected from pyridine, DIEA, TEA, t-BuONa and K ² CO ³ , and the suitable solvent is selected from acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, MTBE, EtOAc, i-PrOAc, DCM, toluene, DMF and methanol. In other embodiments, the suitable base is selected from ^Et3N and the suitable solvent is selected from DCM.

According to another embodiment, the second step comprises reacting 1 equivalent of acetylene with 1.2 equivalents of the chloroxime intermediate and 1.3 equivalents of Et ³ N in DCM at room temperature.

According to another embodiment, suitable isoxazole formation conditions comprise combining the compound of formula 4 with an oxidant in a suitable solvent. In some embodiments, said oxidant is [bis (trifluoroacetoxy) iodo] benzene and said solvent is a 1: 1: 1 mixture of methanol, water, and dioxane.

Synthesis of Compounds 1-2 and 1-3

An embodiment of the invention provides a process for preparing a compound of formula I-2:

comprising one or more of the following stages:

a) React a compound of formula 1b:

with methylamine under suitable reductive amination conditions to form a compound of formula 2b:

b) reacting a compound of formula 2b under suitable Boc protection conditions to form the compound of formula 3b:

c) reacting a compound of formula 3b under suitable oxime formation conditions to form the compound of formula 4-i:

d) reacting a compound of formula 4-i under suitable chloroxime formation conditions to form the compound of formula 4-ii:

e) reacting the compound of formula 4-ii with a compound of formula 4-iii

under suitable cycloaddition conditions to form a compound of formula 4-iv:

f) reacting a compound of formula 4-iv with a compound of formula A-5-i:

under suitable coupling conditions to form the compound of formula 5-i:

g) deprotecting a compound of formula 5-i under suitable Boc deprotection conditions, optionally followed by treatment under basic aqueous conditions to form a compound of formula I-2. Another embodiment discloses a process for preparing a compound of formula I-3:

comprising one or more of the following stages:

a) React a compound of formula A-1:

with tetrahydro-2H-pyran-4-amine under suitable reductive amination conditions to form a compound of formula A-2:

b) reacting a compound of formula A-2 under suitable Boc protection conditions to form the compound of formula A-3:

c) reacting a compound of formula A-3 under suitable oxime formation conditions to form the compound of formula A-4:

d) reacting a compound of

under suitable chloroxime formation conditions to form the compound of formula A-4-i:

e) reacting the compound of formula A-4-i with a compound of formula A-4-ii:

under suitable cycloaddition conditions to form the compound of formula A-5:

f) reacting a compound of formula A-5 with a compound of formula A-5-i:

A-5-i

under suitable coupling conditions to form the compound of formula A-6:

g) deprotecting a compound of formula A-6 under suitable Boc deprotection conditions, optionally followed by treatment under basic aqueous conditions to form a compound of formula I-3.

Suitable coupling conditions comprise combining a suitable palladium catalyst with a suitable base in a suitable solvent. Suitable palladium catalysts include, but are not limited to, Pd [P (tBu) a] ² , Pd (dtbpf) Cl ² , Pd (PPha) ² Cl ² , Pd (PCya) ² Cl ² , Pd (dppf) Cl ² and Pd (dppe) Cl ² . Suitable solvents include, but are not limited to, toluene, MeCN, water, EtOH, IPA, 2-Me-THF, or IPAc. Suitable bases include, but are not limited to, K ² CO ³ , Na ² CO ^3, or K ³ PO ⁴ .

Suitable oxime formation conditions consist of a single stage sequence or a two stage sequence. The two-step sequence consists of first deprotecting the ketal group on the compound of formula A-3 in an aldehyde under suitable deprotection conditions, and then forming the oxime of formula A-4 under suitable oxime formation conditions.

The single-step sequence comprises, for example, comprising mixing hydroxylamine, an acid, an organic solvent, and water together. In some embodiments, NH ² OH.HCl is added to a mixture of THF and water. In some embodiments, 1 equivalent of the compound of formula 3-A is combined with 1.1 equivalents of NH ² OH.HCl in a 10: 1 v / v mixture of THF / water.

Suitable deprotection conditions include adding an acid, acetone, and water. Suitable acids include pTSA or HCl, suitable organic solvents include chlorinated solvents (eg, dichloromethane (DCM), dichloroethane (DCE), CH ² O ^2, and chloroform); an ether (eg THF, 2-MeTHF, and dioxane); aromatic hydrocarbons (for example, toluene and xylenes, or other aprotic solvents.

Suitable cycloaddition conditions comprise a suitable base (for example, pyridine, DIEA, TEA, t-BuONa or K ² CO ³ ) and a suitable solvent (for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, MTBE, EtOAc, i- PrOAc, DCM, toluene, DMF and methanol.

Suitable chloroxime formation conditions include adding HCl in dioxane to a solution of the oxime in the presence of NCS in a suitable solvent selected from non-protic solvents (DCM, DCE, THF and dioxane), aromatic hydrocarbons (eg toluene, xylenes ) and alkyl acetates (eg, isopropyl acetate, ethyl acetate).

Suitable Boc deprotection conditions include adding a suitable Boc deprotection agent (eg, TMS-Cl, HCl, TBAF, H ³ PO ^4, or TFA) and a suitable solvent (eg, acetone, toluene, methanol, ethanol , 1-propanol, isopropanol, CH ² O ² , EtOAc, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and diethyl ether). In some embodiments, suitable Boc deprotection conditions comprise adding a suitable Boc deprotection agent selected from HCl, TFA, and a suitable solvent selected from acetone, toluene, isopropyl acetate, tetrahydrofuran, or 2-methyltetrahydrofuran.

Suitable Boc protection conditions include (Boc) ² O, a suitable base and a suitable solvent. Suitable bases include, but are not limited to, Et ³ N, diisopropylamine, and pyridine. Suitable solvents include, but are not limited to, chlorinated solvents (eg, dichloromethane (DCM), dichloroethane (DCE), CH ² Cl ^2, and chloroform); an ether (eg THF, 2-MeTHF, and dioxane); aromatic hydrocarbons (eg, toluene and xylenes, or other aprotic solvents. In some embodiments, the suitable base is Et ³ N, the suitable solvent is DCM, tetrahydrofuran, or 2-methyltetrahydrofuran. In certain embodiments, the protection conditions include adding 1 0.05 equivalents of (Boc) ² O in 2-methyltetrahydrofuran or DCM.

Suitable reductive amination conditions include adding a reducing agent selected from NaBH ⁴ NaBH ⁴ , NaBH ³ CN or NaBH (OAc) ³ in the presence of a solvent selected from dichloromethane (DCM), dichloroethane (DCE), an alcoholic solvent selected from methanol, ethanol, 1-propanol, isopropanol or a non-protic solvent selected from dioxane, tetrahydrofuran or 2-methyltetrahydrofuran and optionally a

base selected from Et ³ N or diisopropylethylamine. In some embodiments, suitable reductive amination conditions comprise adding 1.2 equivalents of NaBH ⁴ capsules in the presence of Et ³ N in MeOH.

Another aspect of the present disclosure provides a compound of Formula II:

or a pharmaceutically acceptable salt thereof,

wherein each R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9a, R9b, R10a, R10b, and R10c is independently

hydrogen or deuterium, and

at least one of R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9a, R9b, R10a, R10b and R10c is deuterium.

In some embodiments, R9a and R9b are the same. In other embodiments, R9a and R9b are deuterium, and R1a, R1b, R1c, R2,

R3a, R3b, R3c, R4, R5, R6, R7, R8, R10, R11a, R11b, R12a, R12b, R13a, R13b, R14a and R14b are deuterium or hydrogen. In yet another embodiment, R9a and R9b are deuterium, and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R10, R11a, R11b, R12a, R12b,

R13a, R13b, R14a and R14b are hydrogen.

In one embodiment, R9a, R9b, R10a, R10b, and R10c are the same. In another embodiment, R9a, R9b, R10a, R10b, and R10c are deuterium, and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, and R8 are deuterium or hydrogen. In some embodiments, R9a, R9b,

Ri ° a, R10b and R10c are deuterium, and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7 and R8 are hydrogen.

In other embodiments, R10a, R10b, and R10c are the same. In one embodiment, R10a, R10b, and R10c are deuterium, and R1a, R1b,

R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9a and R9b are deuterium or hydrogen. In yet another embodiment, R10a, R10b, and R10c are deuterium, and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9a, and R9b are In some embodiments, R1a, R1b, R1c, R2, R3a, R3b and R3c are the same. In another embodiment R1a, R1b, R1c, R2, R3a, R3b and

R3c are deuterium, and R4, R5, R6, R7, R8, R9a, R9b, R10a, R10b, and R10c are deuterium or hydrogen. In yet another embodiment,

R1a, R1b, R1c, R2, R3a, R3b and R3c are deuterium, and R4, R5, R6, R7, R8, R9a, R9b, R10a, In another embodiment, R6 is deuterium and R1a, R1b, R1c, R2, R3a , R3b, R3c, R4, R5, R7, R8, R9a, R9b, R10a, R10b and R10c deuterium or hydrogen. In yet another embodiment, R6 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R7, R8, R9a,

R9b, R10a, R10b and R10c are hydrogen.

In other embodiments, R2 is deuterium and R1a, R1b, R1c, R3a, R3b and R3c, R4, R5, R6, R7, R8, R9a, R9b, R10a, R10b, and R10c are deuterium or hydrogen. In another embodiment, R2 is deuterium and R1a, R1b, R1c, R3a, R3b and R3c, R4, R5, R6, R7, R8 R9a, R9b,

R10a, R10b and R10c are hydrogen.

In another embodiment, R7 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R8, R9a, R9b, R10a, R10b, and R10c are

deuterium or hydrogen. In other embodiments, R7 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R8, R9a, R9b,

R10a, R10b, R10c are hydrogen.

In yet another embodiment, R8 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R9a, R9b, R10a, R10b, and R10c are

deuterium or hydrogen. In another embodiment, R8 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R9a, R9b,

R10a, R10b, R10c are hydrogen.

In some embodiments, at least one of R10a, R10b, or R10c are the same. In another embodiment, at least one of R10a,

R10b or R10c are deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9a and R9b are deuterium or hydrogen. In

still another embodiment, at least one of R10a, R10b or R10c are deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7,

R8, R9a and R9b are hydrogen.

In some embodiments, at least two of R10a, R10b, or R10c are the same. In another embodiment, at least two of R10a,

R10b or R10c are deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9a and R9b are deuterium or hydrogen. In

Still another embodiment, at least two of R10a, R10b or R10c are deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7,

R8, R9a and R9b are hydrogen.

In another embodiment, R1a, R1b, R1c, R3a, R3b, and R3c are the same. In some embodiments, R1a, R1b, R1c, R3a, R3b, and R3c

they are deuterium, and R2, R4, R5, R6, R7, R8, R9a, R9b, R10a, R10b, and R10c are deuterium or hydrogen. In yet another embodiment,

R1a, R1b, R1c, R3a, R3b and R3c is deuterium and R2, R4, R5, R6, R7, R8, R9a, R9b, R10a, R10b and R10c are hydrogen.

In yet another embodiment, R4 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R5, R6, R7, R8, R9a, R9b, R10a, R10b and R10c are

deuterium or hydrogen. In other embodiments, R4 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R5, R6, R7, R8, R9a, R9b,

R10a, R10b and R10c are hydrogen.

In another embodiment, R5 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R6, R7, R8, R9a, R9b, R10a, R10b, and R10c are

deuterium or hydrogen. In yet another embodiment, R5 is deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R6, R7, R8, R9a,

R9b, R10a, R10b and R10c are hydrogen.

In another embodiment, at least one of R9a or R9b are the same. In other embodiments, at least one of R9a or R9b are

deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R10a, R10b and R10c are deuterium or hydrogen. In some

Embodiments, at least one of R9a and R9b are deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R10a, R10b,

R10c are hydrogen.

In one embodiment, R6, R9a, and R9b are the same. In some embodiments, R6, R9a, and R9b are deuterium, and R1a, R1b, R1c,

R2, R3a, R3b, R3c, R4, R5, R7, R8, R10a, R10b, R10c are deuterium or hydrogen. In other embodiments, R6, R9a, and R9b are

deuterium, and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R7, R8, R10a, R10b and R10c are

In some embodiments, R2, R10a, R10b, and R10c are the same. In another embodiment, R2, R10a, R10b, and R10c are deuterium, and

R1a, R1b, R1c, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9a and R9b are deuterium or hydrogen. In yet another embodiment, R2, R10a,

R10b and R10c are deuterium, and R1a, R1b, R1c, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9a and R9b are hydrogen.

In some embodiments, R7 and at least two of R10a, R10b, or R10c are the same. In another embodiment, R7 and at least two

de R10a, R10b or R10c are deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c, R4, R5, R6, R8, R9a and R9b are deuterium or hydrogen.

In yet another embodiment, R7 and at least two of R10a, R10b or R10c are deuterium and R1a, R1b, R1c, R2, R3a, R6, R8, R9a and R9b are hydrogen.

In some embodiments, R1a, R1b, R1c, R2, R3a, R3b, R3c, and at least one of R10a, R10b, or R10c are the same. In other

embodiment, R1a, R1b, R1c, R2, R3a, R3b, R3c, and at least one of R10a, R10b or R10c are deuterium and R4, R5, R6, R7, R8, R9a and

R9b are deuterium or hydrogen. In yet another embodiment, R1a, R1b, R1c, R2, R3a, R3b, R3c, and at least one of R10a, R10b, or

R10c are deuterium and R4, R5, R6, R7, R8, R9a and R9b are hydrogen.

In some embodiments, R1a, R1b, R1c, R3a, R3b, R3c, and R5 are the same. In another embodiment, R1a, R1b, R1c, R3a, R3b, R3c

and R5 are deuterium and R2, R4, R6, R7, R8, R9a, R9b, R10a, R10b and R10c are deuterium or hydrogen. In yet another embodiment,

R1a, R1b, R1c, R3a, R3b, R3c and R5 are deuterium and R2, R4, R6, R7, R8, R9a, R9b, R10a, R10b and R10c are hydrogen.

In other embodiments, R4 and R6 are the same. In another embodiment, R4 and R6 are deuterium and R1a, R1b, R1c, R2, R3a, R3b, R3c;

R5, R7, R8, R9a R9b R10a R10b and R10c are deuterium or hydrogen. In yet another embodiment, R4 and R6 are deuterium and R1

R1b, R1c, R2, R3a, R3b, R3c R5, R7, R8, R9a, R9b, R10a, R10b and R10c are hydrogen.

In one embodiment, R2, R5, R9a and R9b are the same. In some embodiments, R2, R5, R9a, and R9 R1c, R3a, R3b, R3c, R4, R6, R7, R8, R10a, R10b, and R10c are deuterium or hydrogen. In another embodiment, R2, R5, R9a and R9b are

deuterium and R1a, R1b, R1c, R3a, R3b, R3c, R4, R6, R7, R8, R10a, R10b and R10c are hydrogen.

In yet another embodiment, R1a, R1b, R1c, R2, R3a, R3b, R3c, R5, R6, R9a, R9b, R10a, R10b and R10c are the same. In some Embodiments R1a, R1b, R1c, R2, R3a, R3b, R3c, R5, R6, R9a, R9b, R10a, R10b and R10c are deuterium, and R4, R7 and R8 are deuterium or hydrogen. In other embodiments, R1a, R1b, R1c, R2, R3a, R3b, R3c, R5, R6, R9a, R9b, R10a, R10b and R10c is deuterium and R4, R7 and R8 are hydrogen.

In some embodiments, the variables are as represented in the compounds of the disclosure that include compounds in the tables below.

Table I

The compounds of this invention include those generally described herein and are further illustrated by classes, subclasses, and species disclosed herein. As used herein, the following definitions will apply unless otherwise noted. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed .: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

As described herein, a specified numerical range of atoms includes any integer within it. For example, a group that has 1-4 atoms could have 1, 2, 3, or 4 atoms.

As described herein, the compounds of the invention may be optionally substituted with one or more substituents, as generally illustrated herein or as exemplified by particular classes, subclasses, and specific species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted", whether or not preceded by the term "optionally", refers to the substitution of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have one substituent at each substitutable position in the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specific group, the substituent may be the same or different in each position. Substituent combinations provided for by the present invention are preferably those that result in the formation of stable or chemically feasible compounds.

Unless otherwise indicated, a substituent connected by a bond represented from the center of a ring means that the substituent can be attached to any position on the ring. In example i below , for example, J1 can be attached to any position on the pyridyl ring. For bicyclic rings, a bond represented through both rings indicates that the substituent can be linked from any position on the bicyclic ring. In example ii below , for example, J1 can be linked to the 5-membered ring (at the nitrogen atom, for example) and the 6-membered ring.

The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow their production, detection, recovery, purification, and use for one or more of the purposes. disclosed in this document. In some embodiments, a stable compound or a chemically feasible compound is one that is not substantially altered when maintained at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least one week.

The term "aliphatic" or "aliphatic group", as used herein, means a linear (ie, unbranched), branched or cyclic chain, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains a or more unsaturation units, which have a single point of attachment to the rest of the molecule.

Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms, and in still other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. The aliphatic groups can be substituted or unsubstituted, linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and ferc-butyl. Aliphatic groups can also be cyclic or have a combination of linear or branched and cyclic groups. Examples of such types of aliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, -CH ² -cyclopropyl, CH ² CH ² CH (CH ³ ) -cyclohexyl.

The term "cycloaliphatic" (or "carbocycle" or "carbocyclyl") refers to a monocyclic C ³ -C ⁸ hydrocarbon or a bicyclic C ⁸ -C ¹² hydrocarbon that is fully saturated or contains one or more unsaturation units, but it is non-aromatic, having a single point of attachment to the rest of the molecule at which any single ring in said bicyclic ring system has 3-7 members. Examples of cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

The term "heterocycle", "heterocyclyl" or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the "heterocycle," "heterocyclyl," or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorous, and each ring in the system contains 3 to 7 ring members.

Examples of heterocycles include, but are not limited to, 3-1H-benzoimidazol-2-one, 3- (1-alkyl) -benzoimidazol-2-one, 2-tetrahydrofuranoyl, 3-tetrahydrofuranoyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholine, 3-thiomorpholine, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidyl 4-thiazolidinyl, 1 -imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithian, and 1,3-dihydro-imidazol-2-one.

Cyclic groups, (eg, cycloaliphatic and heterocycles), can be linearly condensed, bridged, or spirocyclic.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorous, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorous or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen from a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).

The term "unsaturated", as used herein, means that a residue has one or more unsaturation units. As one of skill in the art would know, unsaturated groups can be partially unsaturated or fully unsaturated. Examples of partially unsaturated groups include, but are not limited to, butene, cyclohexene, and tetrahydropyridine. Fully unsaturated groups can be aromatic, anti-aromatic, or non-aromatic. Examples of fully unsaturated groups include, but are not limited to, phenyl, cyclooctatetraen, pyridyl, thienyl, and 1-methylpyridin-2 (1H) -one.

The term "alkoxy" or "thioalkyl", as used herein, refers to an alkyl group, as defined above, is attached through an oxygen ("alkoxy") or sulfur atom ("thioalkyl ").

The terms "haloalkyl", "haloalkenyl", "haloaliphatic" and "haloalkoxy" mean alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. This term includes perfluorinated alkyl groups, such as -CF ³ and -CF ² CF ³ .

The terms "halogen", "halo" and "hal" mean F, Cl, Br or I.

The term "aryl" used alone or as part of a larger residue as in "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members , in which at least one ring of the system is aromatic and in which each ring of the system contains from 3 to 7 ring members. The term "aryl" can be used interchangeably with the expression "aryl ring".

The term "heteroaryl", used alone or as part of a larger residue as in "heteroaralkyl" or "heteroarylalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, in where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and where each ring in the system contains 3 to 7 ring members. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Examples of heteroaryl rings include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzoimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 2-isoxazolyl, 2 -oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (for example, 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg, 5-tetrazolyl), triazolyl (eg, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl , benzofuryl, benzothiophenyl, indolyl (eg 2-indolyl), pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (for example, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (for example, 1-isoquinolinyl, 3-i soquinolinyl or 4-isoquinolinyl).

The term "heteroaryl" should be understood to include certain types of heteroaryl rings that exist in equilibrium between two different forms. More specifically, for example, species, such as hydropyridine and pyridinone (and also hydroxypyrimidine and pyrimidinone) are intended to fall within the definition of "heteroaryl".

The terms "protecting group" and "protecting group", as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites. In certain embodiments, a protecting group has one or more, or preferably all, of the following characteristics: a) it is selectively added to a functional group with good performance to give a protected substrate that is b) stable to the reactions that occur in one or more of the other reactive sites; and c) can be selectively removed in good yield by reagents that do not attack the regenerated unprotected functional groups. As a person skilled in the art would understand, in some cases, the reagents do not attack other reactive groups of the compound. In other cases, the reagents can also react with other reactive groups on the compound. Examples of protecting groups are detailed in Greene, TW, Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book). The term "nitrogen protecting group", as used herein, refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics illustrated for an earlier protecting group and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, TW, Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999.

In some embodiments, a methylene unit of an alkyl or aliphatic chain is optionally replaced by another atom or group. Examples of such atoms or groups include, but are not limited to, nitrogen, oxygen, sulfur, -C (O) -, -C (= N-CN) -, -C (= NR) -, -C (= NOR) -, -SO- and -SO ² -. These atoms or groups can combine to form larger groups. Examples of such larger groups include, but are not limited to, -OC (O) -, -C (O) CO-, -CO ² -, -C (O) NR-, -C (= N-CN), -NRCO-, -NRC (O) O-, -SO ² NR-, -NRSO ² -, -NRC (O) NR-, -OC (O) NR-, and -NRSO ² NR-, where R is eg H or aliphatic C ^1-6 . It should be understood that these groups can bind to the methylene units of the aliphatic chain through single, double or triple bonds. An example of an optional replacement (nitrogen atom in this case) that is attached to the aliphatic chain through a double bond would be -CH ² CH = N-CH ³ . In some cases, especially at the terminal end, an optional replacement may bind to the aliphatic group via a triple bond. An example of this would be CH ² CH ² CH ² CEN. It should be understood that in this situation, the terminal nitrogen is not attached to another atom.

It should also be understood that the term "methylene unit" can also refer to branched or substituted methylene units. For example, in an isopropyl residue [-CH (CH ³ ) ² ], a nitrogen atom (eg NR) that replaces the first recited "methylene unit" would result in dimethylamine [-N (CH ³ ) ² ]. In cases such as these, one skilled in the art would understand that the nitrogen atom will have no additional atoms attached to it, and the "R" of "NR" would be absent in this case.

Unless otherwise indicated, optional replacements form a chemically stable compound. Optional replacements can occur within the chain and / or at either end of the chain; that is, both at the junction point and / or also at the terminal end. Two optional replacements can also be adjacent to each other within a chain, provided it produces a chemically stable compound. For example, a C ³ aliphatic may optionally be replaced by 2 nitrogen atoms to form -C-NeN. Optional replacements can also completely replace all atoms in a chain. For example, a C ³ aliphatic may optionally be replaced by -NR-, -C (O) - and -NR- to form -NRC (O) NR- (a urea).

Unless otherwise indicated, if replacement occurs at the terminal end, the replacement atom is attached to a hydrogen atom at the terminal end. For example, if a -CH ² CH ² CH ³ methylene unit was optionally replaced with -O-, the resulting compound could be -OCH ² CH ³ , -CH ² OCH ^3, or -CH ² CH ² OH. It should be understood that if the terminal atom does not contain any free valence electrons, then a hydrogen atom is not required at the terminal end (eg -CH ² CH ² CH = O or -CH ² CH ² CEN).

Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, geometric, conformational, and rotational) forms of the structures. For example, the R and S configurations for each asymmetric center, the double bond isomers (Z) and (E), and the conformational isomers (Z) and (E) are included in this invention. As a person skilled in the art would understand, a substituent can freely rotate around any

rotary link. For example, a represented substituent also represents.

Therefore, the individual stereochemical isomers as well as the enantiomeric, diastereomeric, geometric, conformational and rotational mixtures of the present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

In the compounds of this invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen in its naturally abundant isotopic composition. Also unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium in an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least a 50.1% incorporation of deuterium).

"D" and "d" both refer to deuterium.

Additionally, unless otherwise indicated, the structures depicted herein They are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, except for the substitution of hydrogen for deuterium or tritium, or the substitution of a carbon for a 13C or 14C enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

Processes

The processes and compounds described herein are useful for producing ATR inhibitors containing an aminopyrazine-isoxazole core. The general synthetic procedures shown in the schemes herein are useful for generating a wide range of chemical species that can be used in the manufacture of pharmaceutical compounds.

SCHEME A

Stage 1

The compound of formula I can be prepared according to the steps indicated in Scheme A. Step 1 represents the use of a readily available aldehyde / ketal as a starting point for the preparation of compounds of formula I, IA and IB. The reductive amination between compound 1 and a suitable primary amine, under conditions known to those skilled in the art, leads to compound 2 where a benzylamine motif has been installed. For example, imines can be formed by combining an amine and an aldehyde in a suitable solvent, such as dichloromethane (DCM), dichloroethane (DCE), an alcoholic solvent (eg, methanol, ethanol), or a non-protic solvent (eg, dioxane). or tetrahydrofuran (THF)). These imines can then be reduced by known reducing agents, including, but not limited to, NaBH4, NaBH ³ CN, and NaBH (OAc) 3 (see JOC 1996, 3849). In some embodiments, 1.05 equivalents of amine are combined with 1 equivalent of aldehyde in methanol. In other embodiments, 1.2 equivalents of amine are combined with 1 equivalent of aldehyde in methanol. This step is then followed by reduction with 0.6 to 1.4 (such as 1.2) equivalents of NaBH4. In some cases, if an amine salt is used, base may also be added (eg Et ³ N or diisopropylethylamine).

Stage 2

Step 2 represents the protection of the benzylamine prepared above, using a carbamate-based protecting group, under suitable protection conditions known to those skilled in the art. Various protecting groups, such as Cbz and Boc, can be used. Protection conditions include, but are not limited to, the following:

a) R-OCOCl, a suitable tertiary amine base and a suitable solvent; wherein R is C ^1-6 alkyl optionally substituted with phenyl;

b) R (CO ² ) OR ', a suitable solvent and optionally a catalytic amount of base, wherein R and R' are each independently C ^1-6 alkyl optionally substituted with phenyl;

c) [RO (C = O)] ² O, a suitable base and a suitable solvent.

Examples of suitable bases include, but are not limited to, Et ³ N, diisopropylamine, and pyridine. Examples of suitable solvents include chlorinated solvents (for example, dichloromethane (DCM), dichloroethane (DCE), CH ² Cl ^2, and chloroform), ethers (for example, THF, 2-MeTHF, and dioxane), aromatic hydrocarbons (for example, toluene, xylenes) and other aprotic solvents.

In some embodiments, protection can be accomplished by reacting the benzylamine with (Boc) ² O and Et ³ N in DCM. In some embodiments, 1.02 equivalents of (Boc) ² O and 1.02 equivalents of Et ³ N 1.02 are used. In another embodiment, protection can be accomplished by reacting the benzylamine with (Boc) ² O in 2-MeTHF. In some embodiments, 1.05 equivalents of (Boc) ² O are used.

Stage 3

Step 3 shows how the ketal functional group is then converted to 3 into oxime 4 in a single step. This direct conversion of ketal to oxime is not extensively described in the literature and it will be appreciated that this step could also be performed in a two-step sequence, transiting through the aldehyde after ketal deprotection using methodologies known to those of skill in the art.

Oxime formation conditions comprise mixing together hydroxylamine, acid, optionally a dehydrating agent and an alcoholic solvent. In some embodiments, the acid is a catalytic amount. In some embodiments, the acid is pTSA or HCl, the dehydration agent is molecular sieves or dimethoxyacetone, and the alcoholic solvent is methanol or ethanol. In some embodiments, hydroxylamine hydrochloride is used, in which case no additional acid is required. In other embodiments, the desired product is isolated through a biphasic treatment and optionally precipitation or crystallization. If a biphasic treatment is used, no dehydrating agent is needed.

In another embodiment, the oxime formation conditions consist of mixing hydroxylamine, an acid, an organic solvent and water together. Examples of suitable organic solvents include chlorinated solvents (for example, dichloromethane (DCM), dichloroethane (DCE), CH ² O ^2, and chloroform), ethers (for example, THF, 2-MeTHF, and dioxane), aromatic hydrocarbons (for example , toluene, xylenes) and other aprotic solvents. In some embodiments, 1.5 equivalents of hydroxylamine hydrochloride are used, the organic solvent is 2-MeTHF, and the water is buffered with Na ² SO ⁴ . In another embodiment, 1.2 equivalents of hydroxylamine hydrochloride are used, the organic solvent is THF.

In some embodiments, suitable deprotection conditions comprise adding catalytic amounts of para-toluenesulfonic acid (pTSA), acetone, and water; and then form the oxime using conditions known to a person skilled in the art. In other embodiments, a single stage sequence is used. In some embodiments, the single-step sequence comprises adding NH ² OH.HCl and a mixture of THF and water. In some embodiments, 1 equivalent of the compound of formula 3 is combined with 1.1 equivalents of NH ² OH.HCl in a 10: 1 v / v mixture of THF / water.

Stage 4

Step 4 illustrates how oxime 4 is then transformed and involved in a [3 + 2] cycloaddition for isoxazole 5. This transformation can be performed in a single vessel but requires two distinct steps. This first stage is an oxidation of the oxime functional group on a nitrone, or a similar intermediate with the same degree of oxidation, for example a chloroxime. This reactive species then reacts with an alkyne in a cycloaddition [3 + 2] to form the isoxazole adduct.

In some embodiments, suitable isoxazole-forming conditions consist of two steps, the first step comprising reacting the compound of formula 4 under suitable chloro-oxime formation conditions to form a chloro-oxime intermediate; the second step comprising reacting the chloroxime intermediate with acetylene under suitable cycloaddition conditions to form a compound of formula 5.

In some embodiments, the chloroxime formation conditions are selected from

a) N-chlorosuccinimide and a suitable solvent;

b) potassium peroxymonosulfate, HCl and dioxane; and

c) Sodium hypochlorite and a suitable solvent

Examples of suitable solvents include, but are not limited to, non-protic solvents (eg, DCM, DCE, THF, 2-MeTHF, MTBE, and dioxane), aromatic hydrocarbons (eg, toluene, xylenes), and alkyl acetates (eg. , isopropyl acetate, ethyl acetate).

Product isolation can be achieved by adding an antisolvent to a solution of a compound of formula 5. Examples of suitable solvents for isolating the chloroxime intermediate include mixtures of Suitable solvents (EtOAc, IPAC) with hydrocarbons (for example, hexanes, heptane, cyclohexane) or aromatic hydrocarbons (for example, toluene, xylenes). In some embodiments, heptane is added to a solution of chloroxime in IPAC.

Suitable cycloaddition conditions consist of combining chloroxime with acetylene with a suitable base and a suitable solvent. Suitable solvents include protic solvents, aprotic solvents, polar solvents, and nonpolar solvents. Examples of a suitable solvent include, but are not limited to, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, MTBE, EtOAc, i-PrOAc, DCM, toluene, d Mf, and methanol. Suitable bases include, but are not limited to, pyridine, DIEA, TEA, t-BuONa, and K ² CO ³ . In some embodiments, suitable cycloaddition conditions comprise adding 1.0 equivalents of chloroxime, 1.0 equivalents of acetylene, 1.1 equivalents of Et3N in DCM.

Product isolation can be achieved by adding an antisolvent to a solution of a compound of formula 5. Examples of suitable solvents for isolating chloroxime include mixtures of suitable solvents (EtOAc, IPAC) with hydrocarbons (eg, hexanes, heptane, cyclohexane) or aromatic hydrocarbons (for example, toluene, xylenes). In some embodiments, heptane is added to a solution of chloroxime in IPAC.

Stage 5

Step 5 represents the final step or steps of the preparation of compounds of formula I. When group R4 is bromine, intermediate 5 can be cross-coupled by Suzuki acid or boronic esters, under conditions known to those skilled in the art, to form compounds where R4 is an aryl, heteroaryl, or alternative moieties resulting from the metal-assisted coupling reaction. When intermediate 5 is properly functionalized, a deprotection step can be performed to remove the protecting groups and generate the compounds of formula I.

Metal-assisted coupling reactions are known in the art (see for example, Org.Proc. Res. Dev. 2010, 30-47). In some embodiments, suitable coupling conditions comprise adding 0.1 equivalents of Pd [P (tBu) ³ ] ² ; 1 equivalent of boronic acid or ester; and 2 equivalents of sodium carbonate in a 2: 1 v / v ratio of acetonitrile / water at 60-70 ° C. In other embodiments, suitable coupling conditions comprise adding 0.010-0.005 equivalents of Pd (dtbpf) Cl ² , 1 equivalent of boronic acid or ester and 2 equivalents of potassium carbonate in 7: 2 v / v toluene and water at 70 ° C.

The final product can be treated with a metal remover (silica gel, functionalized resins, charcoal) (see for example Org. Proc. Res. Dev. 2005, 198-205). In some embodiments, the product solution is treated with Biotage MP-TMT resin.

The product can also be isolated by crystallization from an alcoholic solvent (eg methanol, ethanol, isopropanol). In some embodiments, the solvent is ethanol. In other embodiments, the solvent is isopropanol.

The deprotection of Boc groups is known in the art (see, for example, Protecting Groups in Organic Synthesis, Greene and Wuts). In some embodiments, suitable deprotection conditions are hydrochloric acid in acetone at 35-45 ° C. In other embodiments, the suitable deprotection conditions are TFA in DCM.

Stage 6

Step 6 illustrates how compounds of formula I are converted to compounds of formula I-A using a base under suitable conditions known to those skilled in the art. In some embodiments, isolation of the free base form of compounds of formula I can be accomplished by adding a suitable base, such as NaOH to an alcoholic acid solution of compounds of formula I to precipitate the product.

Stage 7

Step 7 illustrates how compounds of formula I-A are converted to compounds of formula I-B using an acid under suitable conditions known to those skilled in the art.

In some embodiments, suitable conditions involve adding aqueous HCl to a suspension of compounds of formula I-A in acetone at 35 ° C, then heating to 50 ° C.

SCHEME B: Formation of dl-boronate

Scheme B shows a general synthetic method for the preparation of dl-boronate intermediates. A suitable 1-halo- (isopropylsulfonyl) benzene is treated with a base, such as, but not limited to, NaH, LiHMDS, or KHMDS, followed by inactivation of the anion with a deuterium source, such as D ² O. Thereafter, halogen it is transformed into a suitable boronate derivative by, for example, metal mediated cross coupling, catalyzed by, for example, Pd ('Bu ^{3) 2} or Pd (dppf) ChDCM.

SCHEME C: Formation of d6-boronate

Scheme C shows a general synthetic method for the preparation of d6-boronate intermediates. A suitable 1-halo- (methylsulfonyl) benzene is treated with a base, such as, but not limited to, NaH, LiHMDS, or KHMDS, followed by quenching of the anion with a source of deuterium, such as D ³ CI. This reaction is repeated until the desired amount of deuterium has been incorporated into the molecule. The halogen is then transformed into a suitable boronate derivative by, for example, metal mediated cross coupling, catalyzed by, for example, Pd ('Bu ³ ) ² or Pd (dppf) Cl ² DCM.

SCHEME D: Formation of d7-boronate

Scheme D shows a general synthetic method for the preparation of d7-boronate intermediates. 4-Bromobenzenethiol is treated with a base, such as, but not limited to, NaH, LiHMDS, or KHMDS, followed by inactivation of the anion with a source of deuterium, such as 1,1,1,2,3,3,3-heptadeuterium -2-iodine-propane. The sulfide is then oxidized to the corresponding sulfone using, for example, mCPBA or Oxone. The halogen is then transformed into a suitable boronate derivative by, for example, metal mediated cross coupling, catalyzed by, for example, Pd ('Bu ^{3) 2} or Pd (dppf) ChDCM.

SCHEME E: Formation of deuterated boronate of the aryl ring

Scheme E shows a general synthetic method for the preparation of boronate intermediates where the aryl ring is replaced with a deuterium. A suitable 1-iodo-4-bromo-aryl derivative is treated with a substituted thiol, such as propane-2-thiol, under metal catalyzed coupling conditions using a catalyst, such as CuI. The sulfide is then oxidized to the corresponding sulfone using, for example, mCPBA or Oxone. The bromide is then transformed into a suitable boronate derivative by, for example, metal mediated cross coupling, catalyzed by, for example, Pd ('Bu ³ ) ² or Pd (dppf) Cl ² DCM. The remaining substituent is then converted to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd-C in a deuterium gas atmosphere. Furthermore, 1-bromo- (isopropylsulfonyl) benzene can be treated with a base, such as, but not limited to, NaH, LiHMDS, or KHMDS, followed by inactivation of the anion with a deuterium source, such as D ² O. Thereafter, the Bromide is transformed into a suitable boronate derivative by, for example, metal mediated cross coupling, catalyzed by, for example, Pd ('Bu ³ ) ² or Pd (dppf) ChDCM. The remaining substituent is then converted to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd-C in a deuterium gas atmosphere.

SCHEME F: Formation of deuterated boronate of the aryl ring

Scheme F shows another general synthetic method for the preparation of boronate intermediates where the aryl ring is replaced with a deuterium. A substituted 4-bromobenzenethiol is treated with a base, such as, but not limited to, NaH, LiHMDS, or KHMDS, followed by inactivation of the anion with a deuterium source, such as 1,1,1,2,3,3,3 -heptadeuterium-2-iodine-propane. The sulfide is then oxidized to the corresponding sulfone using, for example, mCPBA or Oxone. The halogen is then transformed into a suitable boronate derivative by, for example, metal mediated cross coupling, catalyzed by, for example, Pd ('Bu ³ ) ² or Pd (dppf) Cl ² ' DCM. The remaining substituent is then converted to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd-C in a deuterium gas atmosphere.

SCHEME G: Formation of deuterated boronate of the aryl ring

Scheme G shows another general synthetic method for the preparation of boronate intermediates where the aryl ring is replaced with a deuterium. A substituted 4-bromobenzenethiol is treated with a base, such as, but not limited to, NaH, LiHMDS, or KHMDS, followed by inactivation of the anion with, for example, MeI. The sulfide is then oxidized to the corresponding sulfone using, for example, mCPBA or Oxone. The sulfone is treated with a base, such as, but not limited to, NaH, LiHMDS, or KHMDS, followed by inactivation of the anion with a deuterium source, such as D ³ CI. This reaction is repeated until the desired amount of deuterium has been incorporated into the molecule. The halogen is then transformed into a suitable boronate derivative by, for example, metal mediated cross coupling, catalyzed by, for example, Pd ('Bu ^{3) 2} or Pd (dppf) ChDCM. The remaining substituent is then converted to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd-C in a deuterium gas atmosphere.

SCHEME H: Formation of deuterated oxime intermediates of the aryl ring

Scheme H shows a general synthetic method for the preparation of oxime intermediates where the aryl ring is replaced with a deuterium. The methyl group of a suitably substituted methyl 4-methylbenzoate derivative can be converted to the corresponding dibromide under conditions, such as AIBN catalyzed bromination with NBS. This di-bromide is then hydrolyzed to the corresponding aldehyde, for example using AgNO ³ in acetone / water. Protection of aldehyde as a suitable acetal, for example diethyl acetal, and subsequent conversion of the remaining substituent to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd on C in an atmosphere of deuterium gas gives the deuterated ester intermediate. Ester functionality can be reduced using reagents, such as LiAlH ⁴ , NaBH ⁴ , NaBD ^4, or LiAlD ⁴ to give the corresponding aldehyde. This can be reacted under reductive amination conditions using a suitable amine, such as methylamine or d3-methylamine using a reducing agent, such as NaBH ⁴ or NaBD ⁴ to give the corresponding amine derivative. This can be protected with, for example, a Boc group and the acetal converted to the oxime using, for example, hydroxylamine hydrochloride in THF / water.

SCHEME I: Formation of deuterated oxime intermediates of the aryl ring

Scheme I shows another general synthetic method for the preparation of oxime intermediates where the aryl ring is replaced with a deuterium. The methyl group of a suitably substituted methyl 4-methylbenzoate derivative can be converted to the corresponding dibromide under conditions, such as AIBN catalyzed bromination with NBS. This di-bromide is then hydrolyzed to the corresponding aldehyde, for example using AgNO ³ in acetone / water. Protection of aldehyde as a suitable acetal, for example dimethyl acetal, and subsequent conversion of the remaining substituent to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd on C in a deuterium gas atmosphere, gives the deuterated ester intermediate. The ester functionality can be converted to the corresponding primary amide under conventional conditions, such as heating with a solution of ammonia in methanol. The amide can be reduced to the corresponding amine using reagents not limited to LiAlH ⁴ or LiAlD ⁴ . This can be protected with, for example, a Boc group. NH carbamate can be alkylated under basic conditions using for example NaH, LiHMDS or KHMDS, followed by quenching of the anion with a deuterium source, such as MeI or D ³ CI. Acetal can be converted to the oxime using, for example, hydroxylamine hydrochloride in THF / water.

SCHEME J: Formation of deuterated oxime intermediates of the aryl ring

Scheme J shows another general synthetic method for the preparation of oxime intermediates where the aryl ring is replaced with a deuterium. The methyl group of a suitably substituted methyl 4-methylbenzoate derivative can be converted to the corresponding dibromide under conditions, such as AIBN catalyzed bromination with NBS. This di-bromide is then hydrolyzed to the corresponding aldehyde, for example using AgNO ³ in acetone / water. Protection of aldehyde as a suitable acetal, for example dimethyl acetal, and subsequent conversion of the remaining substituent to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd on C in a deuterium gas atmosphere, gives the deuterated ester intermediate. The ester functionality can be converted to the corresponding primary amide under conventional conditions, such as heating with a solution of ammonia in methanol. The amide can be reduced to the corresponding amine using reagents not limited to LiAlH ⁴ or LiAlD ⁴ . This can be reacted under reductive amination conditions using a suitable amine, such as methylamine, d3 methylamine, formaldehyde or od ² -formaldehyde using a reducing agent, such as NaBH ⁴ or NaBD ⁴ , to give the corresponding amine derivative. This can be protected with, for example, a Boc group. Acetal can be converted to the oxime using, for example, hydroxylamine hydrochloride in THF / water.

SCHEME K: Formation of deuterated oxime intermediates of the aryl ring

Scheme K shows another general synthetic method for the preparation of oxime intermediates where the aryl ring is replaced with a deuterium. The methyl group of a suitably substituted methyl 4-methylbenzoate derivative can be converted to the corresponding dibromide under conditions, such as AIBN catalyzed bromination with NBS. This di-bromide is then hydrolyzed to the corresponding aldehyde, for example using AgNO ³ in acetone / water. Protection of aldehyde as a suitable acetal, for example dimethyl acetal, and subsequent conversion of the remaining substituent to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd on C in a deuterium gas atmosphere, gives the deuterated ester intermediate. This can be reacted under reductive amination conditions using a suitable amine, such as ammonium hydroxide, using a reducing agent, such as NaBH ⁴ or NaBD ⁴ , to give the corresponding amine derivative. This can be protected with, for example, a Boc group and the alkylated NH carbamate under basic conditions using, for example, NaH, LiHMDS or KHMDS, followed by inactivation of the anion with a deuterium source, such as MeI or D ³ CI. The ester can be reduced to the corresponding alcohol using a suitable reducing agent, such as LiBH ⁴ or NaBH ⁴ . The alcohol can be oxidized to the aldehyde using reagents, such as MnO ² or Dess-Martin's periodan. Acetal can be converted to the oxime using, for example, aqueous hydroxylamine.

SCHEME L: Formation of intermediates of deuterated oxime

Scheme L shows a general synthetic method for the preparation of deuterated oxime intermediates. 4- (Diethoxymethyl) benzaldehyde can be reacted under reductive amination conditions using a suitable amine, such as methylamine or d3-methylamine using a reducing agent, such as NaBH ⁴ or NaBD ⁴ to give the corresponding amine derivative. This can be protected with, for example, a Boc group and the acetal converted to the oxime using, for example, hydroxylamine hydrochloride in THF / water.

SCHEME M: Formation of intermediates of deuterated oxime

Scheme M shows another general synthetic method for the preparation of deuterated oxime intermediates. The functionality of methyl 4- (dimethoxymethyl) benzoate ester can be converted to the corresponding primary amide under conventional conditions, such as heating with a solution of ammonia in methanol. The amide can be reduced to the corresponding amine using reagents not limited to LiAlH ⁴ or LiAlD ⁴ . This can be protected with, for example, a Boc group. NH carbamate can be alkylated under basic conditions using for example NaH, LiHMDS or KHMDS, followed by quenching of the anion with a deuterium source, such as MeI or D ³ CI. Acetal can be converted to the oxime using, for example, hydroxylamine hydrochloride in THF / water.

SCHEME N: Formation of intermediates of deuterated oxime

Scheme N shows another general synthetic method for the preparation of deuterated oxime intermediates. The functionality of methyl 4- (dimethoxymethyl) benzoate ester can be converted to the corresponding primary amide under conventional conditions, such as heating with a solution of ammonia in methanol. The amide can be reduced to the corresponding amine using reagents not limited to LiAlH ⁴ or LiAlD ⁴ . This can be reacted under reductive amination conditions using a suitable amine, such as methylamine, d3-methylamine, formaldehyde or d2-formaldehyde using a reducing agent, such as NaBH ⁴ or NaBD ⁴ , to give the corresponding amine derivative. This can be protected with, for example, a Boc group. Acetal can be converted to the oxime using, for example, hydroxylamine hydrochloride in THF / water.

SCHEME O: Intermediate formation of deuterated oxime

Scheme O shows another general synthetic method for the preparation of deuterated oxime intermediates. A 4-substituted benzylmine can be protected with, for example, a Boc group. NH carbamate can be alkylated under basic conditions using for example NaH, LiHMDS or KHMDS, followed by quenching of the anion with a deuterium source, such as MeI or D ³ CI. The ester can be reduced to the corresponding alcohol using a reducing agent suitable, such as LÍBH ⁴ or NaBH ⁴ . The alcohol can be oxidized to the aldehyde using reagents, such as MnO ² or Dess-Martin periodicin. Acetal can be converted to the oxime using, for example, aqueous hydroxylamine.

SCHEME P: Formation of isoxazole derivatives

Scheme P shows a general synthetic method for the preparation of deuterated pyrazinaisoxazole derivatives. 3,5-Dibromopyrazin-2-amine is converted to the corresponding silyl protected alkyne under standard Sonagashira conditions using, for example, Pd (PPh ^{3) 4} and CuI as catalyst. The pyrazine NH ² can then be protected as, for example, the di-Boc derivative. Coupling of the pyrazine bromide with a boronate, for example those indicated in Schemes 1 to ⁶ above, under standard Suzuki cross coupling conditions, followed by removal of the silyl protecting group gives the desired alkyne intermediate. The oximes, such as those indicated in Schemes 7 to 14 above, can be converted to the corresponding chloroximes using, for example, NCS. The alkyne and chloroxime intermediates can be cycloadditioned [3 + 2] to give the corresponding isoxazole under conventional conditions, for example by the addition of Et ³ N. Boc protecting groups can be removed under acidic conditions, such as TFA in DCM or HCl in MeOH / DCM to give the deuterated pyrazine isoxazole derivatives.

SCHEME Q: Formation of deuterated isoxazole derivatives

Scheme Q shows a general synthetic method for the preparation of deuterated isoxazole derivatives. Pyrazine NH ² and benzylamine NH can be protected under conventional conditions using trifluoroacetic anhydride. Halogenation of the isoxazole ring with, for example, NIS, followed by removal of the trifluoroacetate protecting group under basic conditions provides the desired halogenated intermediates. The halogen can then be converted to deuterium by, for example, metal-catalyzed halogen-deuterium exchange using a suitable metal catalyst, such as Pd-C in a deuterium gas atmosphere.

Abbreviations

The following abbreviations are used:

Adenosine triphosphate ATP

Boc tere-butyl carbamate

Cbz Carboxybenzyl

DCM dichloromethane

DMSO dimethyl sulfoxide

Et3N triethylamine

2-MeTHF 2-methyltetrahydrofuran

NMM N-Methyl morpholine

DMAP 4-Dimethylaminopyridine

TMS Trimethylsilyl

MTBE methyl tert-butyl ether

EtOAc ethyl acetate

i-PrOAc isopropyl acetate

IPAC isopropyl acetate

DMF dimethylformamide

DIEA diisopropylethylamine

TEA triethylamine

t-BuONa sodium tert-butoxide

K ² CO ³ potassium carbonate

PG Protective group

pTSA para-toluenesulfonic acid

TBAF Tetra-n-Butylammonium Fluoride

1H NMR proton nuclear magnetic resonance

HPLC high liquid chromatography

performance

CLEM liquid chromatography-spectrometry

masses

TLC thin layer chromatography

Tr retention time

SCHEMES AND EXAMPLES

The compounds of the disclosure can be prepared in light of the specification using steps generally known to those skilled in the art. Compounds can be analyzed by known procedures, including but not limited to LCMS (Liquid Chromatography Mass Spectrometry) and NMR (Nuclear Magnetic Resonance). The following generic schemes and examples illustrate how to prepare the compounds of the present disclosure. The examples are for illustration only and should not be construed as limiting the scope of the invention in any way. 1H NMR spectra were recorded at 400 MHz using a Bruker DPX 400 instrument. Spec. Masses were analyzed on a MicroMass Quattro Micro mass spectrometer operated in single EM mode with electrospray ionization.

Example 1: Synthesis of 2- (4- (5-ammo-6- (3- (4 - ((tetrah¡dro-2H-p¡ran-4-ilmo) metíl) feml) ¡soxazol-5 -¡L) p¡razm-2-¡l) p¡r¡dm-2-M) -2-metílpropanomtr¡lo (Compound I-1)

Method 1:

To a solution of tetrahydropyran-4-amine (100g, 988.7mmol) in MeOH (3.922L) was added 4- (diethoxymethyl) benzaldehyde (196.1g, 941.6mmol) for 2 min at RT. The reaction mixture was stirred at RT for 80 min, until aldimine formation was complete (as seen by NMR). NaBH4 (44.49 g, 1.176 mol) was carefully added over 45 min, keeping the temperature between 24 ° C and 27 ° C by means of an ice bath.

After 75 min at RT, the reaction was complete. The reaction mixture was quenched with 1M NaOH (1L). The reaction mixture was partitioned between brine (2.5L) and TBDME (4L, then 2X1L). The organic phase was washed with brine (500 ml) and concentrated in vacuo. The crude mixture was redissolved in DCM (2L). The aqueous phase was separated, the organic phase was dried over MgSO ⁴ , filtered, and concentrated in vacuo to give the title compound as a yellow oil (252.99 g, 91%).

Method 2:

A solution of N - [[4- (diethoxymethyl) phenyl] methyl] tetrahydropyran-4-amine (252.99 g, 862.3 mmol) and Boc anhydride (191.9 g, 202.0 mL, 879.5 mmol ) in DCM (2,530 l) cooled to 3.3 ° C. Et ³ N (89.00 g, 122.6 ml, 879.5 mmol) was added over 4 min, keeping the internal temperature below 5 ° C. The bath was removed 45 min after the end of the addition. And the reaction mixture was stirred at RT overnight. The reaction mixture was washed sequentially with 0.5M citric acid (1L), a saturated NaHCO ³ solution (1L), and brine (1L). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give a colorless oil (372.38 g, 110%). 1H NMR (400.0 MHz, DMSO); EM (EN +)

Method 3:

Tere-Butyl N - [[4- (Diethoxymethyl) phenyl] methyl] -N-tetrahydropyran-4-yl-carbamate (372.38 g, 946.3 mmol) was dissolved in THF (5L) and water (500 ml). Hydroxylamine hydrochloride (72.34 g, 1.041 mol) was added in one portion and the reaction mixture was stirred overnight at RT. The reaction mixture was partitioned between DCM (5L) and water. The combined organic extract was washed with water (1L x 2). The organic phase was concentrated in vacuo to a volume of approximately 2 l. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a colorless, sticky oil that crystallized after a period of standing under vacuum. (334.42 g, 106%). 1H NMR (400.0 MHz, CDCl3); EM (EN +)

Method 4:

Tere-butyl N - [[4 - [(E) -hydroxyiminomethyl] phenyl] methyl] -N-tetrahydropyran-4-yl-carbamate (334.13 g, 999.2 mmol) was dissolved in isopropyl acetate (3 0.01) (The mixture was heated to 40 ° C to allow all solids to enter solution). N-Chlorosuccinimide (140.1 g, 1,049 mol) was added portionwise over 5 min and the reaction mixture was heated to 55 ° C (external block temperature). After 45 min at 55 ° C, the reaction was complete. The reaction mixture was cooled to RT. The solids were removed by filtration and rinsed with isopropyl acetate (1L). The combined organic extract was washed sequentially with water (1.5L, 5 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo to give a viscous yellow oil (355.9g; 96%) . 1H NMR (400.0 MHz, CDCl3); EM (EN +)

Method 5:

Et ³ N (76.97 g, 106.0 ml, 760.6 mmol) was added over 20 minutes to a solution of N- (5-bromo-3-ethynyl-pyrazin-2-yl) -N-tere- tere-butyl butoxycarbonyl-carbamate (233.0 g, 585.1 mmol) and N - [[4 - [(Z) -C-chloro-N-hydroxycarbonimidoyl] phenyl] methyl] -N-tetrahydropyran-4-yl tere-butyl carbamate (269.8 g, 731.4 mmol) in Dc M (2,330 l) at RT. During the addition of triethylamine, the exotherm was stabilized by cooling the mixture in an ice bath, then the reaction mixture was gradually warmed to RT and the mixture was stirred at RT overnight. The reaction mixture was washed sequentially with water (1.5L, 3x) and brine. The organic extract was dried over MgSO4, filtered and partially concentrated in vacuo. Heptane (1.5 L) was added and the concentration continued to yield 547.63 g of a yellow-orange solid.

542.12 g in ~ 2 vol (1 l) of ethyl acetate were collected. The mixture was heated to 74-75 ° C internally and stirred until all of the solid dissolved. Heptane (3.2L) was added slowly via an addition funnel to the hot solution keeping the internal temperature between 71 ° C and 72 ° C. At the end of the addition, the dark brown solution was pipetted with a little recrystallized product, and the reaction mixture was allowed to cool to RT without any stirring to crystallize overnight. The solid was removed by filtration and rinsed with heptane (2 x 250 ml), then dried in vacuo to yield 307.38 g of the title product (72%). %). 1H NMR (400.0 MHz, CDCl3); EM (EN +)

Method 6:

N - [[4- [5- [3- [bis ( tere -butoxycarbonyl) amino] -6-bromo-pyrazin-2-yl] isoxazol-3-yl] phenyl] methyl] -N-tetrahydropyran-4 was suspended tere-butyl -yl-carbamate (303 g, 414.7 mmol) and 2-methyl-2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridyl] propanonitrile (112.9 g, 414.7 mmol) in MeCN (2 l) and H ² O (1 l). Na ² CO ³ (414.7 ml of 2M, 829.4 mmol) was added, followed by Pd [P (tBu) 3] 2 (21.19 g, 41.47 mmol) and the reaction mixture was degassed with N2 for 1 h. The reaction mixture was placed under a nitrogen atmosphere and heated at 70 ° C (block temperature) for 4 h (internal temperature fluctuating between 60 ° C and 61 ° C). The reaction was cooled to room temperature and stirred at RT overnight. The reaction mixture was partitioned between EtOAc (2L) and water (500ml). The combined organic extract was washed with brine (500 ml), filtered through a celite pad and concentrated to reduced pressure to a volume of approximately 3 l. The solution was dried over MgSO4, filtered, and partially concentrated in vacuo. IPrOH (1.5L) was added and the solvent was removed in vacuo to produce the desired product as a light brown foam (405g).

400g in ~ 5 vol (2L) iPrOH was collected and the mixture was heated at 80 ° C until the solid dissolved. The dark brown solution was pipetted and the reaction mixture was allowed to cool slowly to RT overnight. The solid was removed by filtration and rinsed with iPrOH (2 x 250 ml) and petroleum ether (2 x 200 ml). The resulting solid was suspended in petroleum ether (2.5L), filtered off and dried under vacuum. The resulting solid was dissolved in DCM (2.5 l) and slowly stirred for 1 hr with 30 g of SPM32 (3-mercaptopropyl ethyl sulfide silica). Silica was filtered through a florisyl layer and rinsed with DCM. The procedure was repeated twice, then the DCM solution was concentrated in vacuo to give 238.02 g of a light yellow solid.

Method 7:

N - [[4- [5- [3- [bis (tere-butoxycarbonyl) amino] -6- [2- (1-cyano-1-methyl-ethyl) -4-pyridyl] pyrazin-2-yl was dissolved ] texa-butyl] isoxazol-3-yl] phenyl] methyl] -N-tetrahydropyran-4-yl-carbamate (238 g, 299.0mmol) in Dc M (2,380 l). TFA (500 ml, 6,490 mol) was added at RT over 3 min. The reaction mixture was stirred at RT for 3.5 h. The reaction mixture was concentrated under reduced pressure, then azeotropically distilled with heptane (2 x 300 ml). The oil was then suspended in abs EtOH. (2.5L) and filtered. The solid was dissolved in a mixture of ethanol (1,190 l) and water (1,190 l). Potassium carbonate (124.0g, 897.0mmol) in water (357.0ml) was added to the solution and the mixture was stirred at RT overnight.

The solid was filtered off, washed with water (2.5L) and dried at 50 ° C in vacuo to give 108.82g of the title compound (Compound I-1) as a yellow powder . (73%)

Methods 6a and 7a

K2CO3 ac.

2. crystallization

-1

-one

A mixture of N - [[4- [5- [3- [bis (tere-butoxycarbonyl) amino] -6-bromo-pyrazin-2-yl] isoxazol-3-yl] phenyl] methyl] -N-tetrahydropyran- Tere-butyl 4-yl-carbamate (110.0g, 151mmol), K ² CO ³ (41.6g, 301mmol) and 2-methyl-2- [4- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) -2-pyridyl] propanonitrile (41.0 g, 151 mmol) in toluene (770 ml) and water (220 ml) was stirred and degassed with N ² for 30 min at 20 ° C. Catalyst Pd (dtbpf) Cl ² (1.96 g, 3.01 mmol) was added and the mixture was degassed for an additional 10 min. The mixture was heated to 70 ° C until the reaction was complete. The mixture was cooled to room temperature, diluted with water (220 ml), and filtered through a pad of Celite. The organic phase was concentrated to remove most of the solvent. The concentrate was diluted with / -PrOH (550 ml). The resulting suspension was stirred for at least 1 h and then the solid was collected by filtration to provide a brown powder. The solid was dissolved in toluene (990 ml) and stirred with Biotage MP-TMT resin (18.6 g) for 2 h at room temperature. The resin was removed by filtration. The filtrate was concentrated then diluted with / - PrOH (550 ml) and then concentrated again. / '- PrOH (550 ml) was added and stirred for 1 h at room temperature. The suspension was cooled to 5 ° C and the solid was collected by filtration, then dried to provide N - [[4- [5- [3- [bis (ferc-butoxycarbonyl) amino] -6- [2- (1 -cyano-1-methyl-ethyl) -4-pyridyl] pyrazin-2-yl] isoxazol-3-yl] phenyl] methyl] -N-tetrahydropyran-4-yl-carbamate (Compound I-1) (81.9 g; 68%, yield, HPLC purity 98.7% area) as a cream-colored powder.

Change of form for Compound I-1 * HCl * 1.5 H ^two OR

A suspension of N - [[4- [5- [3- [bis (ferc-butoxycarbonyl) amino] -6- [2- (1-cyano-1-methyl-ethyl) -4-pyridyl] pyrazin-2- yl] isoxazol-3-yl] phenyl] methyl] -N-tetrahydropyran-4-yl-carbamate (Compound I-1) (36.0 g, 72.6 mmol) in CH ³ CN (720 ml ) was stirred at room temperature (20 ° C) in a flask equipped with mechanical stirring. A 1M aqueous HCl solution (72.6 ml; 72.6 mmol) was added. The suspension was stirred at room temperature for 20 h. The solid was collected by filtration. The filter cake was washed with CH ³ CN (3 x 50 mL), then dried under vacuum with high humidity for 2 h to provide Compound I-HCVM. 5 H ² O (30.6 g; yield 74%) , purity of 98.8% area according to HPLC) in the form of a yellow powder. 1H NMR (400 MHz, DMSO) 89.63 (d, J = 4.7 Hz, 2H), 9.05 (s, 1H), 8.69 (d, J = 5.2 Hz, 1H), 8 , 21 (s, 1H), 8.16 - 8.03 (m, 3H), 7.84 (t, J = 4.1 Hz, 3H), 7.34 (bs, 2H), 4.40 - 4.18 (m, 2H), 3.94 (dd, J = 11.2, 3.9 Hz, 2H), 3.32 (t, J = 11.2 Hz, 3H), 2.17 - 2 , 00 (m, 2H), 1.81 (s, 6H), 1.75 (dd, J = 12,1,4,3 Hz, 2H).

Example______ 2 _______ Synthesis ______ of______ 3-r3-r4-rdideuterium (methylamino) methylphenylisoxazol-5-ill-5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (Compound II-1)

Step 1: 5-Bromo-3 - ((trimethylsilyl) ethynyl) pyrazin-2-amine

(Trimethylsilyl) acetylene (1,845 g, 2,655 ml, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (compound i ) (5 g, 19.77 mmol) in DMF ( 25 ml). Then, triethylamine (10.00g, 13.77ml, 98.85mmol), copper (I) iodide (451.7mg, 2.372mmol) and Pd (PPh ^{3) 4} (1,142g, 0,) were added. 9885 mmol) and the resulting solution was stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water, and the layers were separated. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with water, dried (MgSO ⁴ ), and concentrated in vacuo. The residue was purified by column chromatography eluting with 15% EtOAc / petroleum ether to give the product as a yellow solid (3.99 g, 75% yield). 1H NMR (400.0 MHz, DMSO) 80.30 (9H, s), 8.06 (1H, s); MS (EN +) 271.82.

Step 2: Tere-Butyl N-Ierc-Butoxycarbonyl-N- [5-bromo-3 - ((trimethylsilyl) ethynyl) pyrazin-2-yl] carbamate

5-Bromo-3- (2-trimethylsilylethynyl) pyrazin-2-amine (2.85 g, 10.55 mmol) was dissolved in DCM (89.06 ml) and treated with Boc anhydride (6.908 g, 7.272 ml, 31.65 mmol), followed by DMAP (128.9 mg, 1,055 mmol). The reaction was allowed to stir at room temperature for 2 hours. The mixture was then diluted with DCM and NaHCO ³ and the layers were separated. The aqueous layer was further extracted with DCM, dried (MgSO ⁴ ), filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with dichloromethane to give the desired product as a colorless oil (4.95g, 99% yield). 1H NMR (400.0 MHz, DMSO) 80.27 (9H, s), 1.42 (18H, s), 8.50 (1H, s); MS (EN +) 472.09.

Step 3: terebutyl tert-Butyl N- (3-ethynyl-5- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) N-tert-butoxycarbonyl-carbamate

W- [5-Bromo-3- (2-trimethylsilylethynyl) pyrazin-2-yl] -N-tert-butoxycarbonyl (3 g, 6.377 mmol) and (4-isopropylsulfonylphenyl) boronic acid (1.491 g, 6.536 mmol) were dissolved. in MeCN / water (60/12 ml). K ³ PO ⁴ (2.706 g, 12.75 mmol) was added and the reaction mixture was degassed with a flow of nitrogen (5 cycles). Pd [P (tBu) ³ ] ² (162.9 mg, 0.3188 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quickly poured into a mixture of ethyl acetate (500 ml), water (90 ml) and 1% aqueous sodium metabisulfite at 4 ° C, stirred well and the layer was separated. The organic fraction was dried over MgSO ⁴ , filtered, and the filtrate was treated with 3-mercaptopropyl ethyl sulfide on silica (0.8 mmol / g, 1 g), preabsorbed on silica gel, then purified by chromatography on column on silica gel eluting with 30-40% EtOAc / petroleum ether. Solvents were concentrated in vacuo to leave the product as a viscous yellow oil, which was triturated with petroleum ether to produce the product as beige crystals (1.95 g, 61% yield); 1H NMR (400 MHz, DMSO) 8 1.20 (m, 6H), 1.39 (s, 18H), 3.50 (m, 1H), 5.01 (s, 1H), 8.03 (m , 2H), 8.46 (m, 2H) and 9.37 (s, 1H).

Stage 4: 4- (Dimethoxymethyl) benzamide

A mixture of methyl 4- (dimethoxymethyl) benzoate (3.8g, 18.08mmol) and 7M NH ³ in MeOH (30mL 7M, 210.0mmol) in a tightly sealed tube was heated to 110 ° C for 22 hours. An additional portion of 7M NH ³ in MeOH (20mL 7M, 140.0mmol) was added and the reaction heated at 135 ° C for 23 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo . The residue was again subjected to the reaction conditions (7M NH ³ in MeOH (30 ml of 7M, 210.0 mmol) at 115 ° C) for an additional 16 hours. The solvent was removed in vacuo and the residue was triturated in Et ² O. The resulting precipitate was isolated by filtration to give the sub-title compound as a white solid (590 mg, 17% yield). The filtrate was purified by column chromatography (ISCO Companion, 40g column, eluting with 0-100% EtOAc / petroleum ether, 10% MeOH / EtOAc, loaded with EtOAc / MeOH) to give an additional portion of the product. of the subtitle as a white solid (225 mg, 6% yield). Total isolated (815 mg, 23% yield); 1H NMR (400 MHz, DMSO) 83.26 (s, 6H), 5.44 (s, 1H), 7.37 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H) , 7.84 - 7.91 (m, 2H) and 7.98 (s, 1H) ppm; MS (EN +) 196.0.

Stage 5: Dideuterium- [4- (dimethoxymethyl) phenyl] methanamine

LDIH ⁴ (12.52 ml of 1M, 12.52 mmol) was added dropwise to a stirred solution of 4- (dimethoxymethyl) benzamide (815 mg, 4.175 mmol) in THF (20 ml) at 0 ° C in a nitrogen atmosphere. The reaction was heated under reflux for 16 hours, then cooled to room temperature. The reaction was stopped by sequential addition of D ² O (1 ml), 15% NaOH in D ² O (1 ml), and D ² O (4 ml). The resulting solid was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was dried by azeotropic distillation with toluene (x 3) to give the sub-title compound as a yellow oil (819 mg), which was used without further purification; 1H NMR (400 MHz, DMSO) ⁸ 3.23 (s, ^6H), 5.36 (s, 1H) and 7.30 to 7.35 (m, 4H) ppm; MS (ES +) 167.0.

Step 6: W- [D¡deuter¡o- [4- (d¡metox¡met¡l) feml] met¡l] tere-butyl carbamate

Et ³ N (633.7 mg, 872.9 pl, 6.262 mmol) was added to a stirred suspension of dideuterium- [4- (dimethoxymethyl) phenyl] methanamine (765 mg, 4.175 mmol) in THF (15 mL) at 0 ° C. The reaction was allowed to stir at this temperature for 30 minutes, then Boc ² O (956.8 mg, 1.007 mL, 4.384 mmol) was added portionwise. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (ISCO Companion, 120 g column, eluting with 0 to 50% EtOAc / petroleum ether, loaded with DCM) to give the subtitle product as a colorless oil (1.04 g, ^{8 8} % yield); 1H NMR (400 MHz, DMSO) ⁸ 1.40 (s, 9H), 3.23 (s, ^6H), 5.36 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.0Hz, 2H) and 7.38 (s, 1H) ppm.

Step 7: W- [Duterde- [4- (dmethoxymethyl) feml] metyl] -W-methyl-tere-butyl carbamate

LiHMDS (1M in THF) (1.377 mL of 1M, 1.377 mmol) was added dropwise to a stirred solution of tere-butyl W- [dideuterium- [4- (dimethoxymethyl) phenyl] methyl] carbamate (300 mg , 1.059 mmol) in THF (5 ml) at -78 ° C. The solution was stirred at this temperature for 10 minutes, then iodomethane (225.4 mg, 98.86 pl, 1.588 mmol) was added dropwise and the mixture was allowed to warm to room temperature for 1 hour. The reaction was again cooled to -78 ° C and LiHMDS (1M in THF) (635.4 µl of 1M, 0.6354 mmol) was added. After 10 minutes, iodomethane (105.2 mg, 46.14 pl, 0.7413 mmol) was added and the reaction was allowed to warm to room temperature for ⁶ hours. The mixture was diluted with EtOAc and the organic layer was washed with saturated aqueous NaHCO ³ (x 2) and brine (x 1), dried (MgSO ⁴ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 24 g column, eluting with 0 to 30% EtOAc / petroleum ether, loaded in DCM) to give the subtitle product as a colorless oil (200 mg, 63% yield); 1H NMR (400 MHz, DMSO) ⁸ 1.41 (d, J = 27.7 Hz, 9H), 2.76 (s, 3H), 3.24 (s, ^6H), 5.37 (s, 1H), 7.23 (d, J = 7.9 Hz, 2H) and 7.37 (d, J = 8.0 Hz, 2H) ppm.

Stage 8: W- [D¡deuter¡o- [4- [h¡drox¡¡mmomet¡l] feml] met¡l] -W- (met¡l) tere-butyl carbamate

Hydroxylamine hydrochloride (51.15 mg, 0.7361 mmol) was added to a stirred solution of ferc-butyl W- [dideuterium- [4- (dimethoxymethyl) phenyl] methyl] -W-methylcarbamate (199 mg, 0.6692 mmol) in THF (10 mL) / water (1,000 mL) and the reaction was allowed to stir at room temperature for 4 hours. The reaction was partitioned between DCM and brine and the layers were separated. The aqueous layer was extracted with DCM (x 2) and the combined organic extracts were washed with brine (x 1), dried (MgSO ⁴ ), filtered, and concentrated in vacuo to give the subtitle compound as a solid white in color (180 mg, 100% yield); 1H NMR (400 MHz, Dm So) 81.41 (d, J = 24.6 Hz, 9H) 2.76 (s, 3H), 7.25 (d, J = 8.1 Hz, 2H), 7 , 58 (d, J = 8.0 Hz, 2H), 8.13 (s, 1H) and 11.20 (s, 1H) ppm; MS (EN +) 211.0 (M-Boc).

Step 9: N - [[4- [Chlorine-W-hydroxyl-carbommidel] feml] -d¡deuterio-metM] -W-methyl-tere-butyl carbamate

Ferc-butyl W- [dideuterium- [4- [hydroxyiminomethyl] phenyl] methyl] -W- (methyl) carbamate (178 mg, 0.6683 mmol) in DMF (2 mL) was treated with NCS (89.24 mg , 0.6883 mmol) and the reaction was heated at 65 ° C for 1 hour. The reaction was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (x 2) and the combined organic extracts were washed with brine (x 4), dried (MgSO ⁴ ), filtered, and concentrated in vacuo to give the subtitle compound as a solid of white (188 mg, 94% yield); 1H NMR (400 MHz, DMSO) 8 1.42 (d, J = 24.7 Hz, 9H), 2.78 (s, 3H), 7.32 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.2 Hz, 2H) and 12.36 (s, 1H) ppm.

Stage 10: W - [[4- [5- [3- [B¡s (fere-butox¡carboml) ammo] -6- (4-¡soprop¡lsulfomlfeml) p¡razm-2-¡l] ¡soxazol -3-l] feml] -d¡deuter¡o-met¡l] -N-metíl-carbamato de tere-butílo

Et ³ N (36.31 mg, 50.01 pl, 0.3588 mmol) was added dropwise to a stirred solution of N-ferc-butoxycarbonyl-N- [3-ethynyl-5- (4-isopropylsulfonylphenyl) pyrazin -2-yl] ferc-butyl carbamate (150 mg, 0.2990 mmol) and N - [[4- [chloro-W-hydroxy-carbonimidoyl] phenyl] -dideuterium-methyl] -W-methyl-carbamate of ferc-butyl (89.93 mg, 0.2990 mmol) in anhydrous THF (3 ml) and the reaction mixture was heated at 65 ° C for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc / brine. Water was added until the aqueous layer became transparent and the layers separated. The aqueous layer was extracted with EtOAc (x 1) and the combined organic extracts were washed with brine (x 1), dried (MgSO ⁴ ), filtered, and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0-30% EtOAc / petroleum ether, loaded with DCM) to give the subtitle product as a white solid (134 mg, 59% yield); NMR 1H (400 MHz, DMSO) 8 1.22 (d, J = 6.8 Hz, 6H) 1.32 (s, 18H), 1.43 (d, J = 23.1 Hz, 9H), 2, 82 (s, 3H), 3.56 (pent, 1H), 7.43 (d, J = 8.3 Hz, 3H), 8.02 - 8.03 (m, 3H), 8.06 - 8 , 11 (m, 2H), 8.62 - 8.67 (m, 2H) and 9.51 (s, 1H) ppm; MS (ES +) 666.2 (M-Boc).

Step 11: 3- [3- [4- [Dideuterium (methylamino) methyl] phenyl] isoxazol-5-yl] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (compound II-1)

3M HCl in MeOH (1167 mL of 3M, 3,500 mmol) was added to a stirred solution of W - [[4- [5- [3- [bis (yercbutoxycarbonyl) amino] -6- (4-isopropylsulfonylphenyl) pyrazin- 2-yl] isoxazol-3-yl] phenyl] -dideuterium-methyl] -W-methylcarbamate of ferc-butyl (134 mg, 0.1750 mmol) in DCM (5 ml) and the reaction heated at reflux for 16 hours . The reaction was cooled to room temperature and the resulting precipitate was isolated by filtration and dried in vacuo at 40 ° C to give the HCl di-salt of the title compound as a yellow solid (58.8 mg, 62% yield); 1H NMR (400 MHz, DMSO) 81.20 (d, J = 6.8 Hz, 6H), 2.60 (t, J = 5.4 Hz, 3H), 3.48 (Sept, J = 6 , 8 Hz, 1H), 7.22 (bs, 2H), 7.69 - 7.75 (m, 2H), 7.85 (s, 1H), 7.92 - 7.99 (m, 2H) , 8.08 - 8.15 (m, 2H), 8.37 - 8.42 (m, 2H), 8.97 (s, 1H) and 9.10 (d, J = 5.8 Hz, 2H ) ppm; MS (ES +) 466.2.

Example 3: Synthesis of 3- [3- [4- [d¡deuter¡o- (tr¡deuter¡omet¡lam¡no) metíl] fen¡l] isoxazol-5-il1-5- (4- Soprop¡lsulfon¡lfen¡l) p¡raz¡n-2-am¡na (Compound II-2)

Stage 1: W- [D¡deuter¡o- [4- (d¡metox¡met¡l) fen¡l] met¡l] -I- (tr¡deuter¡omet¡l) ferc-butMo carbamate

LiHMDS (1M in THF) (1.81ml of 1M, 1.181mmol) was added dropwise to a stirred solution of W- [dideuterium

Ferc-butyl [4- (dimethoxymethyl) phenyl] methyl] carbamate (300mg, 1.059mmol) in THF (5ml) at -78 ° C. The solution was stirred at this temperature for 30 minutes, then trideuterium (iodine) methane (198.0 mg, 84.98 µl, 1.366 mmol) was added dropwise and the mixture was allowed to warm to room temperature over 21 hours. The reaction was again cooled to -78 ° C and an additional portion of LiHMDS (1M in THF) (635.4 jl of 1M, 0.6354 mmol) was added. After 15 minutes, additional trideuterium (iodine) methane (76.75 mg, 32.94 jl, 0.5295 mmol) was added and the reaction was allowed to warm to room temperature for 5 hours. The mixture was diluted with EtOAc and the organic layer was washed with saturated aqueous NaHCO ³ (x 2) and brine (x 1), dried (MgSO ⁴ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 24 g column, eluting with 0 to 30% EtOAc / petroleum ether, loaded in DCM) to give the subtitle product as a colorless oil (213 mg, 67% yield); 1H NMR (400 MHz, DMSO) 8 1.36 - 1.42 (m, 9H), 3.22 (s, 6H), 5.35 (s, 1H), 7.21 (d, J = 7, 8 Hz, 2H) and 7.35 (d, J = 7.7 Hz, 2H) ppm.

Stage 2: W- [D¡deuter¡o- [4- [h¡drox¡¡mmomet¡l] feml] met¡l] -W- (tr¡deuter¡omet¡l) tere-butyl carbamate

Hydroxylamine hydrochloride (53.95 mg, 0.7763 mmol) was added to a stirred solution of ferc-butyl W- [dideuterium- [4- (dimethoxymethyl) phenyl] methyl] -W- (trideuteriomethyl) carbamate (212 mg 0.7057 mmol) in THF (10 mL) / water (1,000 mL) and the reaction was allowed to stir at room temperature for 22 hours. The reaction was partitioned between DCM and brine and the layers were separated. The aqueous layer was extracted with DCM (x 2) and the combined organic extracts were washed with brine (x 1), dried (MgSO ⁴ ), filtered, and concentrated in vacuo to give the subtitle compound as a solid white (190 mg, 100% yield); 1H NMR (400 MHz, DMSO) 8 1.41 (d, J = 24.2 Hz, 9H), 7.25 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8 , 0 Hz, 2H), 8.13 (s, 1H) and 11.20 (s, 1H) ppm.

Stage 3: W - [[4- [Chloro-Wh¡drox¡-carbomm¡do¡l] feml] -d¡deuter¡o-met¡l] -W- (tr¡deuter¡omet¡l) carbamate of tere- butylo

Ferc-butyl W- [dideuterium- [4- [hydroxyiminomethyl] phenyl] methyl] -W- (trideuteriomethyl) carbamate (190.0 mg, 0.7054 mmol) in DMF (2 mL) was treated with NCS (94, 19 mg, 0.7054 mmol) and the reaction was heated at 65 ° C for 1 hour. The reaction was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (x 2) and the combined organic extracts were washed with brine (x 4), dried (MgSO ⁴ ), filtered, and concentrated in vacuo to give the subtitle compound as a solid of white (198 mg, 93% yield); 1H NMR (400 MHz, DMSO) 81.41 (d, J = 26.0 Hz, 9H), 7.32 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8, 2 Hz, 2H) and 12.36 (s, 1H) ppm.

Stage 4: W - [[4- [5- [3- [B¡s (tere-butox¡carboml) ammo] -6- (4-¡soprop¡lsulfomlfeml) p¡razm-2-¡l] ¡soxazol -3-¡l] feml] -d¡deuter¡o-met¡l] -W- (tr¡deuter¡omet¡l) tere-but¡lo carbamate

Et ³ N (36.31 mg, 50.01 pl, 0.3588 mmol) was added dropwise to a stirred solution of N-tere-butoxycarbonyl-W- [3-ethinyl-5- (4-isopropylsulfonylphenyl) pyrazin -2-yl] tere-butyl carbamate (150 mg, 0.2990 mmol) and W - [[4- [chloro-W-hydroxycarbonimidoyl] phenyl] -dideuterio-methyl] -W- (trideuteriomethyl) carbamate of fere- butyl (90.84 mg, 0.2990 mmol) in anhydrous THF (3 ml) and the reaction mixture was heated at 65 ° C for 3.5 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc / brine. Water was added until the aqueous layer became transparent and the layers separated. The aqueous layer was extracted with EtOAc (x 1) and the combined organic extracts were washed with brine (x 1), dried (MgSO ⁴ ), filtered, and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 35% EtOAc / petroleum ether, loaded in DCM) to give the subtitle product as a white solid (158 mg, 69% yield); 1H NMR (400 MHz, DMSO) 81.22 (d, J = 6.8 Hz, 6H), 1.44 (d, J = 22.0 Hz, 9H), 3.56 (dt, J = 13, 5, 6.7 Hz, 2H), 7.43 (d, J = 8.2 Hz, 3H), 8.02 (d, J = 6.9 Hz, 2H), 8.08 (d, J = 8.7 Hz, 2H), 8.65 (d, J = 8.8 Hz, 2H) and 9.51 (s, 1H) ppm; MS (ES +) 669.3 (M-Boc).

Step 5: 3- [3- [4- [dideuterium- (trideuteriomethylamino) methyl] phenyl] isoxazol-5-yl] -5- (4-isopropylsulfonylphenyl) pyrazin-2-amine (compound II-2)

3M HCl in MeOH (1.361 ml of 3M, 4.084 mmol) was added to a stirred solution of W - [[4- [5- [3- [bis (terebutoxycarbonyl) amino] -6- (4-isopropylsulfonylphenyl) pyrazin -2-yl] isoxazol-3-yl] phenyl] -dideuterium-methyl] -W- (trideuteriomethyl) carbamate of fere-butyl (157 mg, 0.2042 mmol) in DCM (5 ml) and the reaction was heated to reflux for 16 hours. The reaction was cooled to room temperature and the resulting precipitate was isolated by filtration and dried in vacuo at 40 ° C to give the HCl di-salt of the title compound as a yellow solid (72.5 mg, 66% yield); 1H NMR (400 MHz, DMSO) 8 1.20 (d, J = 6.8 Hz, 6H), 3.48 (dc, J = 13.6, 6.7 Hz, 1H), 7.21 (s , 2H), 7.68 - 7.78 (m, 2H), 7.85 (s, 1H), 7.91 - 7.99 (m, 2H), 8.08 - 8.13 (m, 2H ), 8.36 - 8.42 (m, 2H), 8.96 (s, 1H) and 9.14 (s, 2H) ppm; MS (ES +) 469.1.

Example 4: Synthesis of 5- (4-¡soprop¡lsulfon¡lfen¡l) -3- [3- [4 - [(tr¡deuter¡omet¡lam¡no) met¡l] phenyl] ¡soxazol-5 -illpirazin-2-amine (Compound II-3)

Stage 1: 4 - [(ferc-Butoxycarbon Mammo) metM] methyl benzoate

Et ³ N (1.882g, 2.592ml, 18.60mmol) was added to a stirred suspension of methyl 4- (aminomethyl) benzoate (hydrochloric acid (1)) (1.5g, 7.439mmol) in THF (20 ml) at 0 ° C. The reaction was allowed to stir at this temperature for 30 minutes, then Boc ² O (1.705g, 1.795ml, 7.811mmol) was added portionwise. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The mixture was diluted with EtOAc. The organic layer was washed with 1M aqueous HCl (x 2), saturated aqueous NaHCO ³ (x 2), and brine (x 1). The organic layer was dried (MgSO ⁴ ), filtered and concentrated in vacuo to give the subtitle compound as a white solid, which was used without further purification (1.93 g, 98% yield); 1H NMR (400 MHz, DMSO) 8 1.40 (s, 9H), 3.85 (s, 3H), 4.20 (d, J = 6.1 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.49 (t, J = 6.1 Hz, 1H) and 7.92 (d, J = 8.2 Hz, 2H) ppm; MS (ES +) 251.1 (M-Me).

Stage 2: 4 - [[ferc-Butoxycarboml (trideuteriometM) ammo] metM] methyl benzoate

LiHMDS (1M in THF) (8.112 ml of 1M, 8.112 mmol) was added dropwise to a stirred solution of methyl 4- [ ( tert- butoxycarbonylamino) methyl] benzoate (1.93 g, 7.275 mmol) in THF (10 ml) at -78 ° C. The solution was stirred at this temperature for 30 minutes, then trideuterium (iodine) methane (1,360 g, 9.385 mmol) was added dropwise and the mixture was allowed to warm to room temperature for 3 hours. The reaction was cooled to -78 ° C and an additional portion of LiHMDS (1M in THF) (2.182ml of 1M, 2.182mmol) was added. After 10 minutes, an additional portion of trideuterium (iodine) methane (527.4 mg, 3,638 mmol) was added and the reaction was allowed to warm to room temperature for 17 hours. The mixture was diluted with EtOAc and the organic layer was washed with saturated aqueous NaHCO ³ (x 2) and brine (x 1), dried (MgSO ⁴ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 120 g column, eluting with 0 to 30% EtOAc / petroleum ether, loaded in DCM) to give the sub-title product as a pale yellow oil ( 1.37 g, 67% yield); 1H NMR (400 MHz, DMSO) 81.38 (d, J = 44.2 Hz, 9H), 3.83 (s, 3H), 4.43 (s, 2H), 7.33 (d, J = 8.2 Hz, 2H) and 7.94 (d, J = 8.1 Hz, 2H) ppm; MS (EN +) 268.1 (M-Me)

Stage 3: W - [[4- (H¡drox¡met¡l) feml] met¡l] -W- (tr¡deuter¡omet¡l) tere-butyl carbamate

LÍBH ⁴ (158.5 mg, 7.278 mmol) was added to a stirred solution of methyl 4 - [[tert- butoxycarbonyl (trideuteriomethyl) amino] methyl] benzoate (1.37 g, 4.852 mmol) in THF (10 mL) and the reaction was heated at 85 ° C for 15 hours. An additional portion of LiBH ⁴ (158.5 mg, 7.278 mmol) was added and the reaction stirred at 65 ° C for an additional 7 hours. The reaction mixture was cooled to room temperature, then poured onto crushed ice, and while stirring, 1M HCl was added dropwise until no further effervescence was observed. The mixture was stirred for 10 minutes, then saturated NaHCOaaqueous was added until the mixture was at pH ⁸ . The aqueous layer was extracted with EtOAc (x 3), and the combined organic extracts were dried (MgSO ⁴ ), filtered, and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 120 g column, eluting with 0-100% EtOAc / petroleum ether, loaded in DCM) to give the subtitle product as a colorless oil (1.03 g, 84% yield); 1H NMR (400 MHz, DMSO) ⁸ 1.42 (d, J = 14.6 Hz, 9H), 4.35 (s, 2H), 4.48 (d, J = 5.7 Hz, 2H), 5.15 (t, J = 5.7 Hz, 1H), 7.18 (d, J = 7.9 Hz, 2H) and 7.30 (d, J = 7.7 Hz, 2H) ppm; MS (EN +) 181.1 (MO'Bu).

Step 4: W - [(4-Formilfeml) metyl] -W- (tri-deuteriomethyl) tere-butyl carbamate

MnO ² (5.281 g, 1.051 mL, 60.75 mmol) was added to a stirred solution of W - [[4- (hydroxymethyl) phenyl] methyl] -W- (trideuteriomethyl) carbamate of ferc-butyl (1.03 g, 4,050 mmol) in DCM (10 mL) and the reaction stirred at room temperature for 20 hours. The reaction was filtered through a pad of Celite and washed with DCM. The filtrate was concentrated in vacuo to give the subtitle compound as a colorless oil (891 mg, ⁸⁸ % yield); 1H NMR (400 MHz, DMSO) ⁸ 1.40 (d, J = 43.4 Hz, 9H), 4.48 (s, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 7.9 Hz, 2H) and 10.00 (s, 1H), ppm.

Stage 5: W - [[4- [H¡drox¡¡mmomet¡l] feml] met¡l] -W- (tr¡deuter¡omet¡l) tere-butyl carbamate

Hydroxylamine (466.0 pl of 50% w / v, 7.054 mmol) was added to a stirred solution of ferc-butyl W - [(4-formylphenyl) methyl] -A / - (trideuteriomethyl) carbamate (890 mg, 3,527 mmol) in ethanol (5 ml) and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo and the residue was taken up in water and extracted with EtOAc (x 3). The combined organic extracts were washed with brine (x 1), dried (MgSO ⁴ ), filtered, and concentrated in vacuo. The residue was triturated in petroleum ether and the precipitate was isolated by filtration to give the subtitle product as a white solid (837 mg, 89% yield); 1H NMR (400 MHz, DMSO) ⁸ 1.41 (d, J = 25.8 Hz, 9H), 4.38 (s, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 8.13 (s, 1H) and 11.20 (s, 1H) ppm; MS (EN +) 212.0 (M-'Bu).

Stage 6: W - [[4- [Chlorine-W-hydroxy-carbommyldol] feml] metl] -W- (tr! Deuteriometl) tere-butyl carbamate

Ferc-butyl carbamate (250 mg, 0) was treated W - [[4- [hydroxymethylomethyl] phenyl] metyl] -W- (tri-deuteriomethyl) carbamate (250 mg, 0 , 9351 mmol) in DMF (2.5 mL) with NCS (124.9 mg, 0.9351 mmol) and the reaction heated at 65 ° C for 1 hour. The reaction was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (x 2) and the combined organic extracts were washed with brine (x 4), dried (MgSO ⁴ ), filtered, and concentrated in vacuo to give the subtitle compound as a solid of white (259 mg, 92% yield); 1H NMR (400 MHz, DMSO) 8 1.41 (d, J = 29.6 Hz, 9H), 4.42 (s, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H) and 12.38 (s, 1H), ppm.

Stage 7: W - [[4- [5- [3- [B¡s (ferc-butox¡carboml) ammo] -6- (4-¡soprop¡lsulfomlfeml) p¡razm-2-¡l] ¡soxazol -3-¡l] feml] met¡l] -W- (tr¡deuter¡omet¡l) carbamate of ferc-but¡lo

Et ³ N (48.41 mg, 66.68 pl, 0.4784 mmol) was added dropwise to a stirred solution of W-ferc-butoxycarbonlW- [3-ethinyl-5- (4-l ferrop-butyl carbamate (200 mg, 0.3987 mmol) and W - [[4- [chloro-W-hydroxy-carbon! ferl-butyl carbamate (120.3 mg, 0.3987 mmol) in anhydrous Th F (5 mL) ) and the reaction mixture was heated at 65 ° C for 2.5 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc / brine. Water was added until the aqueous layer became transparent and the layers separated. The aqueous layer was extracted with EtOAc (x 1) and the combined organic extracts were washed with brine (x 1), dried (MgSO ⁴ ), filtered, and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0-20% EtOAc / petroleum ether, loaded in DCM) to give the subtitle product as a white solid (213 , 5 mg, 70% yield); 1H NMR (400 MHz, DMSO) 81.22 (d, J = 6.8 Hz, 6H), 1.31 (s, 18H), 1.43 (d, J = 26.2 Hz, 9H), 3 , 51 -3.60 (m, 1H), 4.47 (s, 2H), 7.42 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 5.2 Hz, 3H), 8.08 (d, J = 8.6Hz, 2H), 8.65 (d, J = 8.6Hz, 2H) and 9.52 (s, 1H) ppm; MS (ES +) 667.4 (M-Boc).

Stage 8: 5- (4-Isoprop¡lsulfon¡lfen¡l) -3- [3- [4 - [(tr¡deuter¡omet¡lam¡no) met¡l] fen¡l] ¡soxazol-5- L] p¡raz¡n-2-am¡na (Compound II-3)

3M HCl in MeOH (1.5 ml of 3M, 4,500 mmol) was added to a stirred solution of W - [[4- [5- [3- [bis (fercbutoxycarbonyl) amino] -6- (4-isopropylsulfonylphenyl) ) Ferz-butyl pyrazin-2-yl] isoxazol-3-yl] phenyl] methyl] -W- (trideuteriomethyl) carbamate (213 mg, 0.2777 mmol) in DCM (6 mL) and the reaction heated at reflux for 15 hours. An additional portion of 3M HCl in MeOH (0.5 ml of 3M, 1,500 mmol) was added and the reaction was heated at reflux for an additional 7 hours. The reaction was cooled to room temperature and the resulting precipitate was isolated by filtration and dried in vacuo at 40 ° C to give the HCl di-salt of the title compound as a yellow solid (97.6 mg, 65% yield); 1H NMR (400 MHz, DMSO) 81.20 (d, J = 6.8 Hz, 6H), 3.47 (tt, J = 14.0, 6.9 Hz, 1H), 4.19 - 4, 25 (m, 2H), 7.23 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.95 (d, J = 8 , 7 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 8.39 (d, J = 8.7 Hz, 2H), 8.97 (s, 1H) and 9, 11 (s, 2H) ppm; MS (ES +) 467.2.

Example 5: Synthesis of 3- [3- [4- (Met¡lam¡nometíl) fenMl¡soxazol-5-Ml-5- [4- [1.2.2.2-tetradeuter¡o-1- (trideuteriometinetillsulfonilfeniHpirazin-2 -amine (Compound II-4)

Stage 1: 1- [4- (Deoxymethyl) phenyl] -W-metyl-methanamine

2M Methylamine in MeOH (288.1 mL, 576.2 mmol) was diluted with methanol (1,000L) and stirred at ~ 20 ° C. 4- (Diethoxymethyl) benzaldehyde (100 g, 480.2 mmol) was added dropwise over 1 minute and the reaction stirred at room temperature for 1.25 hours. Sodium borohydride (29.07 g, 30.76 ml, 768.3 mmol) was added portionwise over 20 minutes while maintaining the temperature between 20 and 30 ° C with an ice-water bath. The reaction solution was stirred at room temperature overnight, then quenched by dropwise addition of NaOH (960.4 mL 1.0M, 960.4 mmol) over 20 minutes. The reaction was stirred for 30 minutes and concentrated in vacuo to remove MeOH. The reaction was partitioned with MTBE (1,200 l) and the phases were separated. The organic phase was washed with water (300.0 ml), dried (Na ² SO ⁴ ) and concentrated in vacuo to give the title compound as a yellow oil (102.9 g, yield 96 %); 1H NMR (400 MHz, CDCla) 81.25 (t, 6H), 2.46 (s, 3H), 3.45 - 3.65 (m, 4H), 3.75 (s, 2H), 5, 51 (s, 1H), 7.32 (d, 2H) and 7.44 (d, 2H) ppm.

Step 2: W - [[4- (D¡etox¡metM) feml] methyl] -W-methyl-tere-butyl carbamate

A 1L glass-lined reactor was equipped with a stirrer on top, a thermocouple, and a cooler. A solution of 1- [4- (diethoxymethyl) phenyl] -W-methylmethanamine (80.0g, 358.2mmol) in DCM (480.0ml) was stirred at 18 ° C. A solution of Boc anhydride (79.75g, 83.95ml, 365.4mmol) in DCM (160.0ml) was added over 10 minutes and the solution was stirred at 20-25 ° C overnight. The reaction mixture was filtered, rinsed with DCM (3 x 50 ml), and the filtrate was concentrated in vacuo to provide the title compound as a pale yellow liquid (116.6 g, quantitative yield); 1H NMR (400 MHz, CDCla) 81.25 (t, 6H), 1.49 - 1.54 (2 xs, 9H), 2.78 -2.83 (2 xs, 3H), 3.50 -3 , 66 (m, 4H), 4.42 (s, 2H), 5.49 (s, 1H), 7.22 (d, 2H) and 7.45 (d, 2H) ppm.

Stage 3: W - [[4- [HydroxNmmometM] feml] metM] -W-metN-tere-butyl carbamate

A biphasic solution of ferc-butyl W - [[4- (diethoxymethyl) phenyl] methyl] -W-methyl-carbamate (50.0 g, 154.6 mmol) in 2-MeTHF (400.0 mL) and Na ² SO ⁴ (100.0 ml 10% w / v, 70.40 mmol) was stirred at 8-10 ° C in a 1L glass-lined reactor. Hydroxylamine hydrochloride (46.38 ml 5.0 M, 231.9 mmol) was added and the biphasic solution was stirred at 30 ° C for 16 hours. The reaction was diluted with MTBE (200.0 ml) and the layers were separated. The organic phase was washed with water (200.0 ml), dried (Na ² SO ⁴ ), filtered and concentrated in vacuo. The residue was diluted with heptane (200.0 ml) and the resulting suspension was stirred at room temperature for 30 minutes. The solid was collected by filtration to give the title compound as a white solid (36.5 g, 89% yield); 1H NMR (400 MHz, CDCh) 81.50 (s, 9H), 2.88 (bs, 3H), 4.60 (s, 2H), 7.26 (d, 2H), 7.52 (d, 2H) and 8.15 (s, 1H) ppm.

Step 4: ^ - [[4-tChloro-W-hydroxy-carbommidoMJfemlJmetMJ-W-metM-tere-butyl carbamate

A suspension of ferc-butyl W-[[4- [hydroxy! Nomethyl] phen!]] -W-methyl-carbamate (100 g, 378.3 mmol) in isopropyl acetate (1,000 l) was stirred at room temperature. W-Chlorosuccinimide (53.04 g, 397.2 mmol) was added and stirred at room temperature for 16 hours. The reaction was partitioned with water (500.0 ml) and the phases were separated. The organic phase was washed with water (500.0 ml) (2x), dried (Na ² SO ⁴ ), filtered, and concentrated in vacuo to remove most of the solvent. Heptane (1,000 L) was added and the mixture was concentrated in vacuo to remove most of the solvent. Heptane (1,000 l) was added and the resulting precipitate was isolated by filtration. The filter cake was washed with heptane (500ml) and air dried to give the title compound as an off-white powder (105.45g, 93% yield); 1H NMR (400 MHz, CDCls) 81.48 (2 xs, 9H), 2.90 (2 xs, 3H), 4.47 (s, 2H), 7.26 (d, 2H), 7.77 ( d, 2H) and 8.82 (s, 1H) ppm.

Stage 5: W - [[4- [5- [3- [B¡s (ferc-butox¡carboml) ammo] -6-bromo-p¡razm-2-yl] ¡soxazol-3-M] feml] metM] -W-metM-ferc-butyl carbamate

A suspension of W-[[4- [chloro-A / -hydrox-carbon¡m¡do¡l] phen¡l] methyl] -A / -methyl-carbamate of ferc-butyl (100, 0 g, 334.7 mmol) and A / -ferc-butoxycarbon! LW- [3-ethynyl-5- (4-propropyl sulfonlfenl) p !raz-2 -L] ferc-butyl carbamate (121.2 g, 304.3 mmol) in DCM (1,212 l) was stirred at room temperature. Triethylamine (33.87g, 46.65ml, 334.7mmol) was added in one portion and the reaction stirred at room temperature for 16 hours. The reaction was partitioned with water (606.0 ml) and the phases were separated. The organic phase was washed with water (606.0 ml), dried (Na ² SO ⁴ ), filtered, and concentrated in vacuo to near dryness. Heptane (363.6 ml) was added and the mixture was concentrated to approximately 300 ml. More heptane (1,212 l) was added and the mixture was heated to 90 ° C with stirring. The mixture was slowly cooled to room temperature and stirred at this temperature for 1 hour. The resulting precipitate was isolated by filtration and the filter cake was washed with heptane (2 x 363.6 ml) and air-dried to give the title compound as a beige solid (181.8 g, yield 90%); 1H NMR (400 MHz, CDCla) 8 1.41 (s, 18H), 1.51 (s, 9H), 2.88 (2 xs, 3H), 4.50 (s, 2H), 7.36 - 7.38 (m, 3H), 7.86 (d, 2H) and 8.65 (s, 1H) ppm.

Step 6: 1-Bromo-4- [1,2,2,2-tetradeuterium-1- (trideuteriometM) etM] sulfaml-benzene

Sodium hydride (246.5 mg, 6,163 mmol) was added portionwise to a stirred solution of 4-bromobenzenethiol (compound xxxi ) (970.9 mg, 5,135 mmol) in DMF (10 mL) at 0 ° C. After stirring at this temperature for 15 minutes, 1,1,1,2,3,3,3-heptadeuterium-2-iodopropane (1 g, 5,649 mmol) was added and the reaction was allowed to warm to room temperature for 18 hours . The reaction was stopped by the addition of water, and the mixture was stirred for 10 minutes. The mixture was extracted with diethyl ether (x 3) and the combined organic extracts were washed with water (x 2) and brine (x 2), dried (MgSO ⁴ ), filtered and concentrated in vacuo to give the compound of the subtitle, which was used directly without further purification assuming 100% yield and purity; 1H NMR (500 MHz, DMSO) 87.25-7.37 (m, 2H) and 7.48-7.55 (m, 2H) ppm.

Step 7: 1-Bromo-4- [1,2,2,2-tetradeuterium-1- (trideuteriomethyl) ethyl] sulfonyl-benzene

MCPBA (2.875 g, 12.83 mmol) was added portionwise to a stirred solution of 1-bromo-4- [1,2,2,2-tetradeuterium-1- (trideuteriomethyl) ethyl] sulfanyl-benzene (1,223 g, 5.134 mmol) in DCM (20 ml) at 0 ° C and the reaction was allowed to warm to room temperature for 17 hours. The mixture was washed with 1M aqueous NaOH (x 2), saturated aqueous Na ² S ² O ³ (x 3), and brine (x 1), dried (MgSO ⁴ ), filtered, and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80g column, eluting with 0 to 40% EtOAc / petroleum ether, loaded in DCM) to give the subtitle compound as a colorless oil (1.19 g, 86% yield); 1H NMR (500 MHz, DMSO) 87.77 - 7.81 (m, 2H) and 7.88 - 7.92 (m, 2H) ppm.

Step 8: 4,4,5,5-Tetramethyl-2- [4- [1,2,2,2-tetradeuterium-1- (trideuteriomethyl) ethyl] sulfonylphenyl] -1,3,2-dioxaborolane

Pd (dppf) Ch.DCM (179.8 mg, 0.2202 mmol) was added to a stirred suspension of 1-bromo-4- [1,2,2,2-tetradeuterium-1- (trideuteriomethyl) ethyl] sulfonyl -benzene (1.19 g, 4.404 mmol), bis (dipinacolate) diboro (1.342 g, 5.285 mmol) and KOAc (1.296 g, 13.21 mmol) in dioxane (10 ml). The reaction was placed under a nitrogen atmosphere by 5 x nitrogen / vacuum cycles and the mixture was heated at 80 ° C for 4.5 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between Et ² O and water, and the layers were separated. The organic layer was dried (MgSO ⁴ ), filtered, and concentrated in vacuo. The residue was dissolved in 30% EtoAc / petroleum ether (35 ml) and 1.2 g of Florosil was added. The mixture was stirred for 30 minutes, then filtered, washing the solids with additional aliquots of 30% EtOAc / petroleum (x 3). The filtrate was concentrated in vacuo and triturated in 10% EtOAc / petroleum ether. The resulting solid was isolated by filtration, washed with petroleum ether and dried in vacuo to give the subtitle compound as an off-white solid (1052.1 mg, 75% yield); 1H NMR (400 MHz, DMSO) 81.33 (s, 12H), 7.87 (d, J = 8.4 Hz, 2H) and 7.94 (d, J = 8.4 Hz, 2H) ppm.

Stage 9: W - [[4- [5- [3- [B¡s (íerc-butox¡carboml) ammo] -6- [4- [1,2,2,2-tetradeuter¡o-1- ( tr¡deuter¡omet¡l) et¡l] sulfomlfeml] p¡razm-2-¡l] ¡soxazol-3-¡l] feml] metM] -W-metM-ertc-butyl carbamate

[1,1'-Bis (di-ferc-butylphosphino) ferrocene] dichloropalladium (II) (106.8 mg, 0.1639 mmol) was added to a mixture of 4,4,5,5-tetramethyl-2- [ 4- [1,2,2,2-tetradeuterium-1- (trideuteriomethyl) ethyl] sulfonylphenyl] -1,3,2-dioxaborolane (1.3 g, 4,098 mmol), N - [[4- [5- [ 3- [bis (ferc-butoxycarbonyl) amino] -6-bromo-pyrazin-2-yl] isoxazol-3-yl] phenyl] methyl] -N-methyl-carbamate of ferc-butyl (2.707 g, 4.098 mmol) and K ² CO ³ (1,133 g, 8,200 mmol) in toluene (9,100 ml), EtOH (2,600 ml) and water (2,600 ml) and the reaction mixture was degassed with a flow of nitrogen (5 cycles). The mixture was heated at 75 ° C for 1.5 hours. The reaction was cooled to room temperature and water (5.2 ml) was added. After stirring, the layers were separated and the organic layer was dried (Na ² SO ⁴ ), filtered, and concentrated in vacuo. The residue was triturated with IPA and the resulting precipitate was isolated by filtration, washed with IPA (3 x 4 ml) and dried under vacuum at 50 ° C to give the title compound as a white solid (2 , 4 g, 76% yield); 1H NMR (400 MHz, CDCh) ⁸ 1.41 (s, 18H), 1.50 (s, 9H), 2.85 -2.89 (m, 3H), 4.50 (s, 2H), 7 , 36-7.38 (m, 3H), 7.87 (d, 2H), 8.09 (d, 2H), 8.35 (d, 2H) and 9.06 (s, 1H) ppm.

Stage 10: 3- [3- [4- (Met¡lam¡nomet¡l) fen¡l] ¡soxazol-5-¡l] -5- [4- [1,2,2,2-tetradeuter¡o -1- (trideuteriomethyl) ethyl] sulfonylphenyl] pyrazin-2-amine (compound II-4)

Concentrated HCl (3,375 g, 2,812 mL of 37% w / w, 34.25 mmol) was added to a solution of W - [[4- [5- [3- [bis (fercbutoxycarbonyl) amino] -6- [4 - [1,2,2,2-tetradeuterium-1- (trideuteriomethyl) ethyl] sulfonylphenyl] pyrazin-2-yl] isoxazol-3-yl] phenyl] methyl] -W-methyl-carbamate of ferc-butyl (2, 2 g, 2.854 mmol) in acetone (28.60 ml) and the reaction heated at reflux for 7 hours. The reaction was cooled to room temperature and the resulting precipitate was isolated by filtration, washed with acetone (2 x 4.5 ml) and dried in vacuo at 50 ° C to give the HCl di-salt of the title compound in form of a yellow solid (1.42 g, 92% yield); 1H NMR (400 MHz, DMSO) ⁸ 2.58 (t, 3H), 4.21 (t, 2H), 5.67 (bs, 2H), 7.74 (d, 2H), 7.85 (s , 1H), 7.94 (d, 2H), 8.10 (d, 2H), 8.38 (d, 2H), 8.96 (s, 1H) and 9.33 (bs, 2H) ppm; MS (ES +) 471.8.

Example 6: Synthesis of 5- (4- (tert-butyl sulfonyl) phenyl) -3- (3- (4 - ((methylamine) methyl) phenyl) soxazole -5-l) p -raz-2-amine (Compound I-2)

Step 1: Preparation of Compound 4-ii

A suspension of ferc-butyl 4 - ((hydroxyimino) methyl) benzyl (methyl) carbamate ( Compound 4-i ) (650g, 2.46mol) in isopropyl acetate (6.5L) was stirred at room temperature . N-Chlorosuccinimide (361 g, 2.71 mol) was added and the reaction temperature was maintained overnight at 20-28 ° C to ensure a complete reaction. The reaction mixture was diluted with water (3.25L) and EtOAc (1.3L) and the phases were separated. The organic phase was washed with water (2 x 3.25 l), dried (Na ² SO ⁴ ) and concentrated to a wet cake. The concentrate was diluted with heptane (9.1L), ~ 2L of solvent was removed and then stirred at room temperature for 2-20h. The solid was collected by filtration. The filter cake was washed with heptane (2 x 975 ml) and dried to provide Compound 4-ii (692 g; 94% yield, 99.2% purity HPLC area) as a colorless powder.

Step 2: Preparation of (5-bromo-3- (3- (4 - (((ferc-butoxycarbonyl) (methyl) amino) methyl) phenyl) isoxazol-5-yl) pyrazin-2-yl) (fercbutoxycarbon! ) ferc-butyl carbamate ( Compound 4-iv )

A suspension of W- (5-bromo-3-ethylplraz-2-l) -W-ferc-butoxycarbon, ferc-butylcarbamate ( Compound 4-iii ) (1, 59kg, 3.99 mol) and 4- (chloro (hydroxyl) methyl) benzyl (tetrahydro-2H-pran-4-l) ferc-butyl carbamate (1.31 kg, 4.39 mol; 1.10 equ¡v.) In CH ² Ch (12.7 l) was stirred at room temperature. Triethylamine (444 g, 611 ml, 4.39 mol) was added to the suspension and the reaction temperature was maintained between 20-30 ° C for 20-48 h to ensure a reaction. ¡Ón complete. The reaction mixture was diluted with water ⁽ 8L) and mixed thoroughly, then the phases were separated. The organic phase was washed with water ⁽⁸ l), dried (Na ² SO ⁴ ) and then concentrated until approximately 1 l of CH ² Cl ² remained. The concentrate was diluted with heptane (3.2 L) and concentrated again at 40 ° C / 0.03 MPa (200 torr) until distillation was observed. The concentrate was stirred and diluted additionally with heptane (12.7 L) to precipitate a solid. The suspension was shaken overnight. The solid was collected by filtration, washed with heptane (2 x 3 l), and then dried to provide Compound 4-iv (2.42 kg; 92%, purity of 100% area according to HPLC) in the form of a light brown powder. 1H NMR (400 MHz, CDCla) ⁸ 8.61 (s, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.31 (m, 3H), 4.46 (bs, 2H ), 2.84 (br, 3H), 1.57 (s, 2H), 1.44 (bs, 9H), 1.36 (s, 18H).

Step 3: Preparation of Compound 5-i

A mixture of (5-bromo-3- (3- (4 - (((ferc-butoxycarbonyl) (methyl) amine) methyl) phen)) soxazol-5-¡ l) p-raz-2-l) (fercbutoxycarbonl) ferc-butyl carbamate ( Compound 4-iv ) (1.00 kg, 1.51 mol), K ² CO ³ (419 g , 3.02 mol) and acid (4- (sopropulful) phenolic) boron (345 g, 1.51 mol) in toluene (7.0 l) and water (2, 0 l) was stirred and degassed with N ² for 30 min. Then 1,1'-b¡s (df-butylphosphino) ferrocen-dichloro-palladium (l) [Pd (dtbpf) Ch; 19.7 g, 30.3 mmol] and degassed for an additional 20 min. The reaction mixture was heated at 70 ° C for at least 1 h to ensure a complete reaction. The reaction mixture was cooled to room temperature, then filtered through Celite. The reaction vessel and the filter bed were rinsed with toluene (2 x 700 ml). The filtrates were combined and the phases were separated. The organic phase was stirred with Botage MP-TMT resin (170 g) for 4-20 h. The resin was removed by filtration through Celite and the filter bed was washed with toluene (2 x 700 ml). The filtrate and washes were combined and concentrated to near dryness, then diluted with / -PrOH (5.75 L) and concentrated again. The concentrate was redissolved in hot / -PrOH (5.75 l) (45 ° C) and then cooled to room temperature with stirring to induce crystallization, then stirred for approximately 16-20 h. The solid was collected by filtration, washed with / -PrOH (2 x 1L) and dried to provide VRT-1018729 (967g; 84%) as a beige powder. 1H NMR (400 MHz, CDCla) ⁸ 9.04 (s, 1H), 8.33 (d, J = ^{8, 6} Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.34 (m, 3H), 4.47 (bs, 2H), 3.25 (Sept, J = 7.0 Hz, 1H) , 2.85 (bd, 3H), 1.47 (s, 9H), 1.38 (s, 18H), 1.33 (d, J = 6.9 Hz, ^6H).

Step 4: Preparation of Compound I-2 • 2HCl

A solution of Compound 5-i (950 g, 1.24 mol) in acetone (12.35 l) was heated to 40 ° C, then concentrated HCl (1.23 kg, 1.02 l of 37 wt%) was added / w, 12.4 mol) at such a rate to maintain the reaction temperature between 40-45 ° C for at least 5 h to ensure a complete reaction. The suspension was cooled to less than 30 ° C and the solid was collected by filtration. The filter cake was washed with acetone (2 x 950.0 ml), then dried to provide Compound I-2 • 2HCl (578 g; yield 87%, purity 99.5% HPLC area) as of a yellow powder. 1H NMR (400 MHz, DMSO) ⁸ 9.53 (da, J = 4.8 Hz, 2H), 8.93 (s, 1H), 8.37 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H), 7.92 (d, J = ^{8, 6} Hz, 2H), 7.84 (s, 1H), 7.75 (d, J = 8 , 3 Hz, 2H), 4.23 - 4.15 (m, 2H), 3.43 (Sept., J = ^{6, 8} Hz, 1H), 2.55 (t, J = 5.3 Hz, 3H), 1.17 (d, J = ^{6, 8} Hz, ⁶ H).

Step 5: Preparation of Compound I-2 • HCl from Compound I-2 • 2HCl

Two-pot process

A stirred suspension of Compound I-2 • 2HCl (874 g, 1.63 mol) in i-PrOH (3.50 l) and water (0.87 l) was heated at 50 ° C for 1-2 hr. cooled to room temperature and stirred for 1-20 h. XRPD was performed on a small sample to ensure that Compound I-2 • 2HCl had been converted to another form. The suspension was cooled to 5 ° C and stirred for 1 hr. The solid was collected by filtration, then the filter cake was washed with 80/20 i- PrOH / water (2 x 874 ml) and briefly dried.

XRPD showed Compound 1-2 • HCl / anhydrate form, the solid was dried to provide Compound I-2 • HCl / anhydrate (836 g, 99% yield, purity 99.2% area according to HPLC) as of a yellow solid. 1H NMR (400 MHz, DMSO) 69.38 (s, 2H), 8.96 (s, 1H), 8.46 - 8.34 (m, 2H), 8.10 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.85 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.23 ( bs, 2H), 4.21 (s, 2H), 3.47 (Sept., J = 6.7 Hz, 1H), 2.58 (s, 3H), 1.19 (d, J = 6, 8 Hz, 6H).

If XRPD showed Compound 1-2 • HCl / hydrate form, the solid was stirred in freshly prepared i-PrOH (3.50 L) and water (0.87 L) at 50 ° C for at least 2 hr until XRPD shows complete conversion to Compound I-2 • HCl / anhydrate. The suspension was then cooled to 5 ° C and stirred for 1 h. The solid was collected by filtration, then the filter cake was washed with 80/20 hPrOH / water (2 x 874 ml), then dried to provide Compound I-2 ^ HCl / anhydrate.

Alternative procedure ( single container) used

Compound I-2 • 2HCl (392 g) was charged to the reactor. IPA / water 4: 1 (8 L) was charged into a reactor and stirred at room temperature overnight. XRPD was used to confirm conversion to the monohydrate form of HCl mono-salt. The mixture was heated to 50 ° C. Seeds of Compound I-2 • HCl / anhydrate (16 g) were added and the mixture was heated to 50 ° C until XRPD confirmed complete conversion to the desired anhydrate form. The mixture was cooled to room temperature, filtered and the solid was washed with 4: 1 IPA / water (2 x 800 ml), then dried to provide Compound I-2 • HCl / anhydrate (343 g, yield of 94%).

Step 4: Alternative Method 1: Preparation of Compound 1-2 Free Base

A solution of Compound 5-i (100g, 131mmol) in DCM (200ml) was stirred at room temperature, then TFA (299g, 202ml, 2.62mol) was added. After 2 hr, the reaction solution was cooled to 5 ° C. The reaction mixture was diluted with EtOH (1.00L) for approximately 5min, resulting in a bright yellow suspension. The suspension was cooled to 10 ° C, then NaOH (1.64L 2.0M, 3.28mol) was added over 30 min, then stirred at room temperature overnight. The solid was collected by filtration, then washed with water (2 x 400 ml), EtOH (2 x 200 ml), then dried to provide the free base of Compound 1-2 (57.0 g, 94% yield). , purity of 99.7% area according to HPLC) in the form of a fine yellow powder. 1H NMR (400 MHz, DMSO) 6 8.95 (s, 1H), 8.39 (d, J = 8.5 Hz, 2H), 7.95 (dd, J = 11.6, 8.4 Hz , 4H), 7.78 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.21 (bs, 2H), 3.72 (s, 2H), 3.47 (Sept, J = 6.8 Hz, 1H), 2.29 (s, 3H), 1.19 (d, J = 6.8 Hz, 6H).

Step 4: Alternative Method 2: Preparation of Compound I-2 • HCl

A suspension of the free base of Compound 1-2 (10.0 g, 21.6 mmol) in acetone (80 ml) was stirred and heated to 35 ° C. An aqueous solution of HCl (2.0 M 11.9 ml, 23.8 mmol) diluted with water (8.0 ml) was added and the mixture was heated at 50 ° C for 4 h. The suspension was allowed to cool to room temperature, then stirred overnight. The solid was collected by filtration. The filter cake was washed with acetone (2 x 20 ml), then dried to provide 10.2 g of Compound 1-2 hydrochloride (95% yield) as a yellow powder.

Example 7: Synthesis of 5- (4- (Isopropylsulfonyl) phenyl) -3- (3- (4- (tetrahydropyran-4-ylamino) methyl) phenyl) isoxazol-5-yl) pyrazin-2-amine (Compound I- 3)

Scheme: Example Synthesis of Compound 1-3

A solution of tetrahydro-2H-pyran-4-amine hydrochloride (1.13 kg, 8.21 mol) in MeOH (14.3 l) was stirred at approximately 20 ° C, then Et ³ N was added ( 1.06 kg, 1.43 L, 8.21 mol). The mixture was stirred for at least 5 min, then terephthalaldehyde diethyl acetal (1.43 kg, 6.84 mol) was added while maintaining the reaction temperature between 20-25 ° C. The mixture was stirred for at least 45 min to form the imine. NaBH ⁴ capsules (414 g, 11.0 mol) were added while maintaining the reaction temperature below about 25 ° C. The mixture was stirred for 1 hr after completion of the addition. The reaction mixture was quenched by adding 1M NaOH (13.7L), then extracted with MTBE. The organic solution was washed with brine (7.13 l), then dried (Na ² SO ⁴ ) and concentrated to provide Compound A-2 (2197 g; 109% yield, 94.4% purity area according to HPLC) as a cloudy oil. Rm N 1H (400 MHz, CDCh) 87.43 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.49 (s, 1H), 4.66 (bs, 1H), 4.03 - 3.91 (m, 2H), 3.82 (s, 2H), 3.69 - 3.47 (m, 4H), 3.38 (td, J = 11.6, 2.1 Hz, 2H), 2.78 -2.65 (m, 1H), 1.90 -1.81 (m, 2H), 1.53 - 1.37 (m, 2H), 1.23 (t, J = 7.1Hz, 6H).

Step 2: Preparation of 4- (diethoxymethibenzyl (tere-butyl tetrahydro-2H-pyran-4-ihcarbamate (A-3)

A mixture of ^^ - (diethoxymethi ^ benziOtetrahydro ^ H-pyran ^ -amine (A-2) (2195 g, 7.48 mol) in CH ² Cl ² (22.0 l) was stirred at 25 ° C, then was added di-f-butyl dicarbonate (1.71 kg, 7.86 mol) was then added ^Et3N (795 g, 1.10 l) while the reaction temperature was maintained between 20 -. 25 ° C The reaction mixture was stirred at about 25 ° C for 12-20 h After completion of the reaction, the mixture was cooled to about 20 ° C and quenched with 0.5M aqueous citric acid (7.48L, 3.74 mol) while maintaining the reaction temperature between 20-25 ° C. The organic phase was collected, washed with sat. NaHCO ³ (6.51 l, 7.48 mol), washed with brine (6 , 59 l) and dried (Na ² SO ⁴ ), then concentrated to provide 4- (d-ethoxymethyl) benzyl (tetrahydro-2H-pran-4-yl) carbamate of ferc-butyl (A-3) (2801 g; 95% yield, purity 98.8% HPLC area) as a thick amber oil 1H NMR (400 MHz, CDCh) 8 7.40 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 5.49 (s, 1H), 4.39 (bs, 3H), 3.93 (dd a, J = 10.8, 3.8 Hz, 2H), 3.67 - 3.47 (m, 4H), 3.40 (ma, 2H), 1.68 - 1.59 (m, 4H), 1.39 (bs, 9H), 1.23 (t, J = 7.1 Hz, 6H).

Step 3: Preparation of tere-butyl (A-4) 4 - ((hydroxyimino) methyl) benzyl (tetrahydro-2H-pyran-4-yl) carbamate

A solution of 4- (detoxymethyl) benzyl (tetrahydric-2H-pran-4-l) ferc-butyl carbamate (A-3) (2.80 kg, 7 , 12 mol) in THF (28.0 l) and water (2.80 l) were stirred at approximately 20 ° C. Hydroxylamine hydrochloride (593 g, 8.54 mol) was added while maintaining the reaction temperature between 20-25 ° C. The reaction mixture was stirred at about 20 ° C for 16-20 hr, then diluted with CH ² O ² (8.4 L) and 50% brine (11.2 L) and stirred for at least 5 min . Then, the phases were separated, the organic phase was washed with 50% brine (2 x 2.8 l), dried (Na ² SO ⁴ ) and concentrated. The concentrate was diluted with MeOH (1.4L) and concentrated again. The concentrate was diluted with MeOH (14.0 L) and transferred to a reaction vessel. The solution was heated to approximately 25 ° C, then water (14.0 l) was added over approximately 1-1.5 h; then about 10 l of water was added, the mixture was seeded and a cloudy suspension was observed. More water (8.4L) was added over 1.5h to further precipitate the product. After maturing, the solid was collected by filtration. The filter cake was washed with heptane (5.6L) and dried to provide 4 ((hydroxyl, non) methyl) benzyl (tetrahydric-2H-pran-4-l) ferc-butyl carbamate (A-4) (1678 g ; 71%, purity 91.5% HPLC area) in the form of an off-white powder. 1H NMR (400 MHz, CDCl3) 88.12 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 4 , 40 (bs, 3H), 3.96 (dd, J = 10.4, 3.6 Hz, 2H), 3.41 (ma, 2H), 1.69 -1.61 (m, 4H), 1.39 (bs, 9H).

Step 4: Preparation of tert-butyl 4- (chloro (hydroxyimino) methyl) benzyl (A-4-i) (tetra-hydro-2H-pyran-4-yl) carbamate

A suspension of 4 - ((hydroxymethyl) methyl) benzyl (tetrahydric-2H-pran-4-l) carbamate of (E) -ferc-but (A-4) (1662 g, 4.97 mol) in / -PrOAc (16.6 l) was stirred at 20 ° C in a reactor. W-Chlorosuccinin (730 g, 5.47 mol) was added, maintaining approximately 20 ° C. The suspension was stirred at about 20 ° C to complete the reaction. The suspension was diluted with water (8.3 l) and stirred to dissolve the solid. The phases were separated and the organic phase was washed with water (8.3 l). The organic phase was concentrated, then diluted with / -PrOAc (831 ml). Heptane (13.3L; 8V) was added slowly to induce crystallization. The thick suspension was then shaken for 1 h. The solid was collected by filtration; the filter cake was washed with heptane (2 x 1.6 l; 2 x 1 v) and dried to provide 4- (chlorine (hydroxy! min) methyl) benzyl (Z) -ferc-butyl (A-4-!) (1628 g; 89%, purity of 98.0% area according to (tetrahydro-2H-pran-4-l)) carbamate HPLC) in the form of a white powder.

Step ______ 5: ______ Preparation ______ of ______ (5-bromo-3- (3- (4 - (((tert-butoxycarbonyl) (tetrahydro-2H-pyran-4-inamino) metihfeninisoxazol-5-inpirazin-2-ih (tert-butoxycarbonylcarbamate) butyl (A-5)

A solution of 4- (chloro (hydroxymethyl) methyl) benzyl (tetrahydric-2H-pran-4-l) carbamate ferc-butyl ( A-4-¡) (1.60 kg, 4.34 mol) and W- (5-bromo-3-et¡n¡lp¡raz¡n-2-¡l) -A / -ferc-butox¡ Ferc-butyl carbonylcarbamate ( Compound A-4-ii ) (1.73 kg, 4.34 mol) in CH ² Cl ² (12.8 l) was stirred at 20 ° C. Et3N (483 g, 665 ml; 4.77 mol) was added and the reaction temperature was kept below 30 ° C. The suspension was stirred at 20 ° C to complete the reaction, then it was diluted with water (8.0 L) and stirred. The phases were separated and the organic phase was washed with water (8.0 l) and then concentrated. / -PrOAc (1.6 L) was added and the mixture was heated to 50 ° C. Heptane (4.0L) was added slowly, then the suspension was allowed to cool to room temperature and stirred overnight. More heptane (7.2 l) was added to the suspension and stirred for 1 h. The solid was collected by filtration. The filter cake was washed with heptane (2 x 1.6 l) and dried to provide (5-bromo-3- (3- (4 - (((ferc-butoxycarbonyl)) ( tetrah¡dro-2H-p¡ran-4-¡l) amino) metíl) feníl) ¡soxazol-5-¡l) p¡raz¡n-2-¡l) (ferc-butox Ferc-butyl (A-5) carbamate (2,478 kg; 78%, purity of 97.8% area according to Hp LC) in the form of a fine brown powder. 1H NMR (400mHz, CDCl3) 88.60 (s, 1H), 7.78 (d, J = 8.3Hz, 2H), 7.31 (m, 3H), 4.42 (ma, 3H ), 4.03-3.82 (m, 2H), 3.38 (bs, 2H), 1.60 (m, 4H), 1.36 (s, 27H).

Step 6: Preparation of tert-butoxycarbonyl (3- (3- (4 - (((ferc-butoxycarbonih (tetrahydro-2H-pyran-4-inamino)) metihfeninisoxazol-5-in-5- (4- (isopropylsulfonihfenihpirazin-2- tert-butyl incarbamate

A mixture of (5-bromo-3- (3- (4 - (((tert-butoxycarbonyl)) (tetrahydro-2H-pran-4-il) amine) methyl! ) phenyl) soxazol-5-l) prazz-2-l) (tert-butoxycarbonyl) tert-butyl carbamate (A-5) (425 g, 582 mmol), K ² CO ³ (161 g, 1.16 mol; 2.0 equ¡v.) and acid (4- (soprop¡lsulfoní) feníl) borón¡co (133 g, 582 mmol) in toluene (2.98 l) and water (850 ml) were stirred and degassed with N ² at room temperature. The catalyst [1,1'-b¡s (d¡-tert-butylfosphino) ferrocene] dichloropalad (II), (Pd (dtbpf) Cl ² ; 1.90 g, 2 91 mmol) was added and the mixture was degassed for an additional 10 min. The mixture was heated to 70 ° C until the reaction was complete. The mixture is cooled to 50 ° C, diluted with water (850 ml) and filtered through a Celite pad. The phases were separated. The organic phase was concentrated, then the residue was diluted with EtOH (1.70 l) and concentrated again. With mixing at 40 ° C, the concentrate was diluted with EtOH (1.70 l) to induce crystallization. The suspension was cooled to 20 ° C and stirred for 4 h. The solid was collected by filtration. The filter cake was washed with EtOH (2 x 425 ml) and dried in the air to provide tert-butoxycarbon (3- (3- (4 - (((tert-butox! carbonyl) (tetrahydro-2H-pran-4-l) amine) metl) fenyl) soxazol-5-l) -5- (4- (soprop) Sulfonyl) phenyl) prazz-2-l) tert-butyl carbamate (A-6) in the form of a beige colored powder. The solid was dissolved in THF (2.13 l) and suspended with Botage MP-TMT resin (48 g) at room temperature. The resin was removed by filtration and the filtrate was concentrated to remove most of the THF. The concentrate was diluted with EtOH (970 ml) and concentrated again to approximately half the original volume. The concentrate was again diluted with EtOH (970 ml) and mixed for 1 h at 40 ° C. The suspension was cooled to room temperature and the solid was collected by filtration, then dried to provide tert- butoxycarbonyl (3- (3- ( 4 - (((tert-butoxycarbonyl) (tetrahydro-2H-pran-4-l) amine) metl) phen)) soxazol-5-l) - 5- (4- (¡soprop¡lsulfon¡l) fen¡l) p¡raz¡n-2-¡l) tert-butylo carbamate (A-6) (416 g; yield of the 86%, purity 99.3% HPLC area) in the form of a white powder. 1H NMR (400 MHz, CDCla) 89.04 (s, 1H), 8.38 - 8.28 (m, 2H), 8.10 - 8.01 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.34 (m, 3H), 4.44 (bs, 2H), 3.94 (dd, J = 10.5, 3.5 Hz, 2H), 3.40 (bs, 2H), 3.25 (Sept., J = 6.8 Hz, 1H), 1.65 (m, 4H), 1.38 (bs, 27H), 1.33 (d, J = 6 , 9 Hz, 6H).

Step 7: Preparation of free base form of 5- (4- (soprop¡lsulfon¡l) fen¡l) -3- (3- (4 - (((tetrah¡dro-2H-p¡ran-4 -¡L) amno) metfenn¡l) soxazol-5-l) p¡razin-2-am¡na (I-3)

A suspension of tert-butoxycarbonyl (3- (3- (4 - (((tert-butoxycarbonyl)) (tetrahydro-2H-pran-4-l) am! no) metyl) phenyl) soxazole-5-l) -5- (4- (sopropyl sulphon) phenyl) prazz-2-l) tert carbamate -butyl (A-6) (410 g; 492 mmol) in CH ² Cl ² (410 ml) was stirred at room temperature in a flask. TFA (841 g, 568 ml; 7.4 mol) was added while maintaining the reaction temperature between 20-25 ° C. The solution was stirred at room temperature for approximately 3 h when the analysis showed the completion of the reaction. The solution was cooled to approximately 5-10 ° C and diluted with EtOH (3.3L) while maintaining the temperature below 20 ° C. An aqueous 5.0 M NaOH solution (1.77 l; 8.85 mol) was added while the reaction temperature was allowed to rise from about 14 ° C to approx. about 42 ° C. The suspension was heated at 70-75 ° C for 6 hr while the distillate was removed. The suspension was allowed to cool to room temperature. The solid was collected by filtration and the filter cake was washed with water (4 x 1.64 l). The filter cake was washed with EtOH (2 x 820 ml) and dried to provide 5- (4- (sopropulfulfyl) phenyl) -3- (3- (4- ( ((tetrahydro-2H-pran-4-l) amine) methyl) phen) soxazol-5-l) prazz-2-amine (Compound I-1) (257 g; yield 98%, purity 99.5% HPLC area) as a powder yellow.

1H NMR (400 MHz, DMSO) 8 8.94 (s, 1H), 8.44 - 8.33 (m, 2H), 7.94 (t, J = 8.2 Hz, 4H), 7.76 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.20 (s, 2H), 3.83 (m, 1H), 3.80 (s, 3H), 3 , 46 (Sept., J = 6.8 Hz, 1H), 3.25 (td, J = 11.4, 2.1 Hz, 2H), 2.66 - 2.54 (m, 1H), 1 , 79 (dd a, 2H), 1.36 - 1.22 (m, 2H), 1.19 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz, DMSO) 8167.57, 151.76, 141.07, 137.58, 135.75, 129.16, 128.53, 126.57, 126.41, 125.69, 124, 52, 102.13, 65.83, 54.22, 52.60, 49.19, 33.18, 15.20.

Analytical data of the compound

INTERMEDIATE

Example 8: Preparation of Oxime 5a

SCHEMA BB:

Stage 1b

MeOH (28.00 l) and 4- (diethoxymethyl) benzaldehyde (Compound 1b) (3500 g, 16.81 mol) were added in a reactor at 20 ° C. Methylamine, 33% in EtOH (1.898 kg, 2.511 l of 33% w / w, 20.17 mol) was added maintaining 20-30 ° C, then stirred for 1.5 hr to form the imine. NaBH ⁴ capsules (381.7 g, 10.09 mol) were added keeping the temperature between 20-30 ° C. It was stirred at room temperature for at least 30 min to ensure a complete reaction. Aqueous NaOH (16.81L 2.0M, 33.62mol) was added maintaining approximately 20 ° C. MTBE (17.50 L) and brine (7.0 L) were added, stirred for at least 5 min, then the phases were allowed to separate. The aqueous layer was extracted with MTBE (7.0 l), then the organic phases were combined and washed with brine (3.5 l), then dried (Na ² SO ⁴ ) and then concentrated to 6 l. The biphasic mixture was transferred to a settling funnel and the aqueous phase was removed. The organic phase was concentrated to provide 1 - (4- (diethoxymethyl) phenyl) -N-methylmethanamine (Compound 2b) (3755g, 16.82mol, 100% yield) as an oil. 1H NMR (400 MHz, CDCla) 87.43 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.49 (s, 1H), 3 , 75 (s, 2H), 3.68-3.46 (m, 4H), 2.45 (s, 3H), 1.23 (t, J = 7.1Hz, 6H).

Stages 2b and 3b

2-MeTHF (15.00 l) and 1- (4- (diethoxymethyl) phenyl) -N-methylmethanamine (Compound 2b) (3750 g, 16.79 mol) were added to a reactor at 20 ° C. A solution of Boc anhydride (3,848 kg, 4,051 L, 17.63 mol) in 2-MeTHF (7,500 L) was added maintaining approximately 25 ° C. It was stirred for at least 30 min to ensure complete conversion to ferc-butyl 4- (diethoxymethyl) benzyl (methyl) carbamate (Compound 3b), then a solution of Na ² SO ⁴ (1,192 kg, 8,395 mol) was added in water (11.25 l). It was heated to 35 ° C, then a solution of hydroxylamine hydrochloride (1,750 kg, 25.18 mol) in water (3.75 l) was added, then stirred for at least 6h to ensure a complete reaction. It was cooled to 20 ° C, stirring was stopped and the aqueous phase was removed. The organic layer was washed with brine (3.75 l), dried (Na ² SO ⁴ ), filtered, and concentrated to approximately 9 l. Crystalline ferc-butyl 4-((hydroxyimino) methyl) benzyl (methyl) carbamate (Compound 5a) (1.0 g portions every 10 min) was added until nucleation was apparent, it was then concentrated to provide a solid suspension. Heptane (3.75 l) was added, then cooled to temp. atmosphere and leaked. Washed with heptane (5.625L), then dried to provide ferc-Butyl 4 - ((hydroxyimino) methyl) benzyl (methyl) carbamate (Compound 5a) (4023g, 15.22mol, 91% yield, purity 97.2% area according to HPLC) as a colorless solid. 1H NMR (400 MHz, CDCla) 88.13 (s, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.25 (da, 2H), 4.44 (bs, 2H) , 2.83 (br, 3H), 1.47 (bs, 9H).

Scheme CC: Synthesis of Intermediate A-4-ii

The compound of formula A-4-ii can be prepared according to the steps indicated in Scheme C. Sonogashira coupling reactions are known in the art (see, eg, Chem. Rev. 2007, 874-922). In some embodiments, suitable Sonogashira coupling conditions comprise adding 1 equivalent of the compound of formula C-1, 1 equivalent of TMS-acetylene, 0.010 equivalents of Pd (PPh ³ ) ² Cl ² , 0.015 equivalents of Cul and 1.20 NMM equivalents in isopropanol. The product can be isolated by adding water to the alcoholic reaction mixture.

Amine salts of a product can be formed by dissolving the amine in a common organic solvent and adding an acid. Examples of suitable solvents include chlorinated solvents (eg, dichloromethane (DCM), dichloroethane (DCE), CH ² Cl ^2, and chloroform), ethers (eg, THF, 2-MeTHF, and dioxane), esters (eg, EtOAc , IPAC) and other aprotic solvents. Examples of suitable acids include, but are not limited to, HCl, H ³ PO ⁴ , H ² SO ⁴ , MSA and PTSA. In some embodiments, the solvent is IPAC and the acid is PTSA. In some embodiments, the acid addition salt is converted back to the free amine base in the presence of a suitable solvent and a suitable base. Suitable solvents include EtOAc, IPAC, dichloromethane (DCM), dichloroethane (DCE), CH ² O ² , chloroform, 2-MeTHF, and suitable bases include NaOH, NaHCO ³ , Na ² CO ³ , KOH, KHCO ³ , K ² CO ³ and Cs ² CO ³ . In some embodiments, the suitable solvent is EtOAc and the suitable base is KHCO3.

The amine of Compound C-2 can be protected with various amine protecting groups, such as Boc ( tert- butoxycarbonyl). The introduction of Boc protecting groups is known in the art (see, for example, Protecting Groups in Organic Synthesis, Greene and Wuts). In some embodiments, suitable conditions involve adding 1.00 equivalent of the amine, 2.10 equivalent of di-tert-butyl dicarbonate, and 0.03 equivalent of DMAP in EtOAc.

The reduction in Pd is achieved by treatment with a metal remover (silica gel, functionalized resins, charcoal). In some embodiments, the proper conditions involve adding charcoal.

The TMS (trimethylsilyl) protecting group in Compound C-3 can be removed under conditions known to one skilled in the art. In some embodiments, the TMS removal conditions comprise reacting the TMS protected compound with a suitable base in a suitable solvent. Examples of suitable solvents include chlorinated solvents (eg, dichloromethane (DCM), dichloroethane (DCE), CH ² Cl ^2, and chloroform), ethers (eg, THF, 2-MeTHF, and dioxane), esters (eg, EtOAc , IPAC), other aprotic solvents and alcoholic solvents (eg MeOH, EtOH, iPrOH). Examples of suitable bases include, but are not limited to, (eg, NaOH, KOH, K ² CO ³ , Na ² CO ³ ). In certain embodiments, suitable conditions comprise adding 1.00 equivalents of the TMS protected acetylene, 1.10 equivalents of K ² CO ³ , EtOAc and EtOH. In some embodiments, the alcoholic solvent, such as EtOH, is added last in the reaction. In some embodiments, the acetylene product is isolated by adding water.

Scheme DD: Example Synthesis of Compound A-4-ii

Step 1: Preparation of 5-bromo-3 - ((tr¡met¡ls¡l¡l) et¡n¡l) p¡raz¡n-2-amína (Compound C-2)

Isopropanol (8.0 l) was charged into a reactor, then stirred and sprayed with a stream of N ² . 3,5-Dibromopyrazin-2-amine (Compound C-1) (2000 g, 7.91 mol), Pd (PPh ³ ) ² Cl ² (56 g, 0.079 mol), CuI (23 g, 0.119 mol) was added ) and NMM (1043 ml, 9.49 mol) in the reactor under a N ² atmosphere. The reaction temperature was adjusted to 25 ° C. The reactor was purged with N ^{2 by} performing at least three N ² vacuum / purge cycles. TMS-acetylene (1.12 L, 7.91 mol) was charged to the reaction mixture and the reaction temperature was kept below 30 ° C. When the reaction was complete, the temperature of the reaction mixture was decreased to 15 ° C, then water (10 L) was added and stirred for at least 2 h. The solid was collected by filtration, washing the solid with 1: 1 IPA / water (2 x 6 l). The filter cake was dried under vacuum, then charged to a reactor and dissolved in EtOAc (12.5 L). PTSA hydrate (1.28 kg, 6.72 mol) as a solid was charged to the reactor. The mixture was stirred at room temperature for at least 5 h, then the solid was collected by filtration, washed with 1: 1 heptane / EtOAc (3.5 l), followed by heptane (3.5 l). The filter cake was dried to provide 5-bromo-3 - ((trimethylsilyl) ethynyl) pyrazin-2-amine (Compound C-2) as a PTSA salt (2356 g, 67% yield, 98 purity). , 9% area according to HPLC). 1H NMR (400 MHz, DMSO) 8 8.12 (s, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 2.29 (s, 3H), 0.26 (s, 9H).

Stages 2 and 3

Step 2: Preparation of N-tert-butoxycarbonyl-N-r5-bromo-3 - ((tertimelsyll) ethynylpyrazin-2-illcarbamate- tert- butyl (Compound C-3)

A solution of PTSA salt of 5-bromo-3 - ((trimethylsilyl) ethynyl) pyrazin-2-amine (Compound C-2) (2350g, 5.31mol) in EtOAc (11.5L) was stirred with a solution ac. 20% w / w KHCO ³ (4.5 kg, 1.5 equiv.) for at least 30 min. The layers were separated and the organic layer was concentrated, then dissolved in EtOAc (7L) and added in a reactor. DMAP (19.5g, 0.16mol) was added, followed by a small addition of a solution of Boc ² O (2436g, 11.16mol) in EtOAc (3L). The reaction was stirred for at least 30 min to ensure a complete reaction, then activated charcoal (Darco G-60, 720 g) and Celite (720 g) were added and stirred for at least 2 h. The mixture was filtered by washing the solid bed with EtOAc (2 x 1.8 l). The filtrate was concentrated to provide W-ferc-butoxycarbonyl-W- [5-bromo-3 - ((trimethylsilyl) ethynyl) pyrazin-2-yl] carbamate ferc-butyl (Compound C-3) which was used directly in the next stage.

Step 3: Preparation of N- (5-bromo-3-ethynylprazraz-2-l) -N-tert-butoxycarbonyl tert-butylcarbamate (Compound A-4-I ¡)

K ² CO ³ (811 g, 5.87 mol) was charged into a reactor, followed by a solution of Compound C-3 (2300 g, 4.89 mol) dissolved in EtOAc (4.6 l), the agitation. EtOH (9.2L) was added slowly and the mixture was stirred for at least 1h to ensure the reaction was complete, then water (4.6L) was added and stirred for at least 2h. The solid was collected by filtration and washed with 1: 1 EtOH / water (4.6L, followed by 2.3L), followed by EtOH (2.3L). The filter cake was dried to provide A / - (5-bromo-3-ethynylpyrazin-2-yl) -W-fercbutoxycarbonylcarbamate (Compound A-4-ii) (1568 g, 78% yield, 97 0.5% area according to HPLC). 1H NMR (400 MHz, CDCh) 88.54 (s, 1H), 3.52 (s, 1H), 1.42 (s, 18H).

Solid forms of Compound I-2

Compound I-2 has has been prepared in various solid forms, including salts and cosolvates. The solid forms of the present disclosure are useful in the manufacture of drugs for the treatment of cancer. One embodiment provides for the use of a solid form described herein to treat cancer. In some embodiments, the cancer is pancreatic cancer or non-small cell lung cancer. Another embodiment provides a pharmaceutical composition comprising a solid form described herein and a pharmaceutically acceptable carrier.

Applicants describe herein five new solid forms of Compound 1-2. The names and stoichiometry for each of these solid forms are provided below in Table S-1:

Table S-1

Solid state NMR spectra were acquired on the Bruker-Biospin 400 MHz Advance III large-caliber spectrometer equipped with a Bruker-Biospin 4 mm HFX probe. Samples were packaged in 4mm ZrO ² rotors (approximately 70mg or less, depending on mix availability). A magic angle spin rate (MAS) of typically 12.5 kHz was applied. The probe head temperature was adjusted to 275K to minimize the effect of friction heating during rotation. Proton relaxation time was measured using the 1H MAS Ti saturation recovery relaxation experiment to establish an adequate recycling delay of the 13C cross-polarization (CP) MAS experiment. The recycling delay of the 13C CP MAS experiment was adjusted to be at least 1.2 times longer than the 1H T ¹ relaxation time measured to maximize the signal to noise ratio of the carbon spectrum. The CP contact time of the 13C CP MAS experiment was adjusted to 2 ms. A linear ramp CP proton pulse (50% to 100%) was used. The Hartmann-Hahn coincidence was optimized on an external reference sample (glycine). SPINAL 64 decoupled carbon spectra were acquired with a field strength of approximately 100 kHz. The chemical shift was contrasted with an external adamantane pattern with its ascending field resonance set at 29.5 ppm.

The XRPD data for Examples 13-14 was measured on the Bruker D8 Advance system (Asset V014333) equipped with a hermetically sealed tube Cu source and a Vantec-1 detector (Bruker AXS, Madison, WI) at room temperature. The X-ray generator was operated at a voltage of 40 kV and a current of 40 mA. The powder sample was placed on a shallow silicone holder. Data was recorded in a reflective scan mode (locked coupler) over a range of 3 ° -40 ° 2 theta with a stage size of 0.0144 ° and a residence time of 0.25 s ( 105 s per stage). Variable divergence slits were used.

Example 10: Compound 1-2 (free base)

The free base of Compound 1-2 can be formed according to the methods described in Example 6, Step 4: Alternative Method 1.

XRPD of Compound 1-2 (free base)

Figure 1a shows the X-ray powder diffractogram of the sample that is characteristic of a crystalline drug substance.

Representative XRPD peaks of the free base of Compound 1-2:

continuation

Thermal analysis of the free base of Compound 1-2

A free base thermogravimetric analysis of Compound 1-2 was performed to determine the percentage of weight loss as a function of time. The sample was heated from room temperature to 350 ° C at a rate of 10 ° C / min on a TGA Q5000 from TA Instruments (Asset V014258). Figure 2a shows the result of the TGA with a one stage weight loss before evaporation or thermal decomposition. From room temperature to 215 ° C, the weight was ~ 1.9%.

Free base differential scanning calorimetry of Compound 1-2

The thermal properties of the free base of Compound 1-2 were measured using the AT DSC Q2000 instrument (Asset V014259). A sample of Compound 1-2 Free Base (1.6900 mg) was weighed into a pre-drilled airtight aluminum container and heated from room temperature to 350 ° C to 10 ° C / min. An endothermic peak was observed at 210 ° C with its starting temperature at 201 ° C (Figure 3a). The enthalpy associated with the endothermic peak is 78 J / g.

Free base solid state NMR of Compound 1-2

13C CPMAS in the free base of Compound 1-2

275K; 1H T1 = 1.30s

12.5 kHz rotation; adamantane ref. 29.5 ppm

For the full spectrum, see Figure 4a.

Representative peaks

continuation

Crystal structure of the free base of Compound 1-2

The free form of Compound 1-2 was prepared from the HCl salt of Compound 1-2. 200 mg of the HCl salt of Compound 1-2 to 1 ml of a ^6N solution of NaOH was added. 20 ml of dichloromethane was used to extract the free form. The dichloromethane layer was dried over K ² CO ³ . The solution was removed by filtration and 5 ml of n-heptane was added. Crystals were obtained by slow evaporation of the solution at room temperature overnight.

Most of the crystals obtained were thin plates. Among them were found some crystals with a prismatic shape.

A prismatic crystal with dimensions of 0.2 x 0.1 x 0.1 mm3 was selected, mounted on a MicroMount and focused on a Bruker APEX II diffractometer. Three batches of 40 separate frames were obtained in reciprocal space to provide an orientation matrix and initial cell parameters. Final cellular parameters were obtained and refined after data collection was completed based on the complete data set. A reciprocal space diffraction dataset was obtained at an angle resolution of 116.96 ° 20 using 0.5 ° steps with 10 s exposure each frame. Data was collected at a temperature of 100 (2) K with a nitrogen flow cryosystem. Integration of intensities and refinement of cellular parameters were achieved using APEXII software.

CRYSTALLINE DATA

Example 11: Compound I-2 • HCl

Compound I-2 • HCl can be formed according to the methods described in Example ⁶ , Step 4: Alternative Method 2 and Example ⁶ , Step 5.

XRPD of Compound I-2 • HCl

Figure 1b shows the X-ray powder diffractogram of the sample that is characteristic of a crystalline drug substance.

Representative XRPD peaks of Compound I-2 • HCl

continuation

Thermal analysis of Compound I-2 • HCl

A thermogravimetric analysis of Compound I-2 • HCl was performed to determine the percentage of weight loss as a function of time. The sample was heated from room temperature to 350 ° C at a rate of 10 ° C / min on a TGA Q5000 from TA Instruments (Asset V014258). Figure 2b shows the result of the TGA with a two-stage weight loss before evaporation or thermal decomposition. From room temperature to 100 ° C, the weight was ~ 1.1%, and from 110 ° C to 240 ° C the weight loss is ~ 0.8%.

Differential scanning calorimetry of Compound I-2 • HCl

The thermal properties of Compound I-2 • HCl were measured using the AT DSC Q2000 instrument (Asset V014259). A sample of Compound I-2 • HCl (3.8110 mg) was weighed into a pre-drilled airtight aluminum container and heated from room temperature to 350 ° C to 10 ° C / min. An endothermic peak was observed at 293 ° C with its starting temperature at 291 ° C (Figure 3b). The enthalpy associated with the endothermic peak is 160.3 J / g. The second endothermic peak is at approximately 321 ° C. Both peaks were paired with sample evaporation and decomposition.

Solid State NMR of Compound I-2 • HCl

15 CPMAS in Compound I-2 • HCl

275K; 12.5 kHz rotation; adamantane ref. 29.5 ppm

For the full spectrum, see Figure 4b.

Representative peaks

Crystal structure of Compound I-2 • HCl

180 mg of Compound I-2 • HCl were added to a vial with 0.8 ml of 2-propanol and 0.2 ml of water. The sealed vial was kept in an oven at 70 ° C for two weeks. Diffraction grade crystals were observed.

A yellow needle-shaped crystal with dimensions of 0.15 x 0.02 x 0.02 mm3 was selected, mounted on a MicroMount and focused on a Bruker APEX II diffractometer (V011510). Three batches of 40 separate frames were obtained in reciprocal space to provide an orientation matrix and initial cell parameters. Final cellular parameters were collected and refinement completed based on the complete data set.

A reciprocal space diffraction dataset was obtained at an angle resolution of 106 ° 20 using 0.5 ° steps with exposure times of 20 s for each frame for low angle frames and 60 s for each frame for frames high angle. The data was collected at room temperature.

To obtain the data in Table 1, dry nitrogen was blown into the glass at a rate of 6 liters / min to keep ambient humidity out. The data in Table 2 was obtained without nitrogen. Integration of intensities and refinement of cellular parameters were performed using APEXII software. The water occupation can vary between 0 and 1.

Elemental analysis of CHN

Elemental analysis of CHN of Compound I-2 • HCl suggests a mono HCl salt.

Example 12: Compound I-2 • 2HCl

Compound I-2 • 2HCl can be formed according to the methods described in Example 6, Step 4.

XRPD of Compound I-2 • 2HCl

XRPD standards were acquired at room temperature in reflection mode using a Bruker D8 Discover system (Asset Tag V012842) equipped with a hermetically sealed tube source and a Hi-Star area detector (Bruker AXS, Madison, WI). The X-ray generator is operated at a voltage of 40 kV and a current of 35 mA. The powder sample is placed on a nickel holder. Two frames with an exposure time of 120 s each are recorded. The data is then integrated over the range of 4.5 ° -39 ° 2 with a stage size of 0.02 ° and merged in a continuous pattern.

Figure 1c shows the X-ray powder diffractogram of the sample that is characteristic of a crystalline drug substance.

Representative XRPD peaks of Compound I-2 • 2HCl

continuation

Thermal analysis of Compound I-2 • 2HCl

A thermogravimetric analysis of Compound I-2 • 2HCl was performed on the TGA model Q5000 AT instrument. Compound I-2 • 2HCl was placed in a platinum sample container and heated at 10 ° C / min at 350 ° C from room temperature. Figure 2c shows the TGA result, demonstrating a 7.0% weight loss from room temperature at 188 ° C, which is consistent with the loss of 1 HCl equivalent (6.8%). The melting / degradation onset temperature is 263 ° C.

Differential scanning calorimetry of Compound I-2 • 2HCl

A thermogram for Lot 3 of Compound I-2 • 2HCl pharmacological substance was obtained using DSC Q2000 from TA Instruments. Compound I-2 • 2HCl was heated at 2 ° C / min at 275 ° C from -20 ° C, and modulated at ± 1 ° C every 60 sec. The DSC thermogram (Figure 3c) reveals an endothermic peak below 200 ° C, which could correspond to the loss of 1 equivalent of HCl. Melting / recrystallization occurs between 215-245 ° C, followed by degradation. Solid State NMR of Compound I-2 • 2HCl

13 C CPMAS in Compound I-2 • 2HCl

275K; 1H T1 = 1.7s

12.5 kHz rotation; adamantane ref. 29.5 ppm

For the full spectrum, see Figure 4c.

Crystal structure of Compound I-2 • 2HCl

180 mg of Compound I-2 • HCl were added to a vial with 0.8 ml of 2-propanol and 0.2 ml of water. The closed vial Hermetically kept in an oven at 70 ° C for two weeks. Diffraction grade crystals were observed.

A yellow needle-shaped crystal with dimensions of 0.15 x 0.02 x 0.02 mm3 was selected, mounted on a MicroMount and focused on a Bruker APEX II diffractometer (V011510). Three batches of 40 separate frames were obtained in reciprocal space to provide an orientation matrix and initial cell parameters. Final cellular parameters were collected and refinement completed based on the complete data set.

A reciprocal space diffraction dataset was obtained at an angle resolution of 106 ° 20 using 0.5 ° steps with exposure times of 20 s for each frame for low angle frames and 60 s for each frame for frames high angle. The data was collected at room temperature. Dry nitrogen was blown into the glass at a rate of 6 liters / min to keep ambient humidity out. Integration of intensities and refinement of cellular parameters were performed using APEXII software.

CRYSTALLINE DATA

Example 13: Compound I-2 • HCl • H ^two OR

Compound I-2 • HCh H ² O can be formed from Compound I-2 • 2 HCl. (E29244-17) A suspension of Compound I-2 • 2 HCl (10.0 g, 18.6 mmol) in isopropyl alcohol (40 mL) and water (10 mL) was heated at 50 ° C for about 1 hr and then cooled below 10 ° C. The solid was collected by filtration. The filter cake was washed with 80/20 isopropyl alcohol / water (2 x 10 mL) and air dried to provide Compound I-2 • HCl • ² H ² O as a yellow powder.

XRPD of Compound I-2 • HCl • H? O

XRPD standards were acquired at room temperature in reflection mode using a Bruker D8 Discover system (Asset Tag V012842) equipped with a hermetically sealed tube source and a Hi-Star area detector (Bruker AXS, Madison, WI). The X-ray generator is operated at a voltage of 40 kV and a current of 35 mA. The powder sample is placed on a nickel holder. Two frames with an exposure time of 120 s each are recorded. The data is then integrated over the range of 4.5 ° -39 ° 2 with a stage size of 0.02 ° and merged in a continuous pattern.

Figure 1d shows the X-ray powder diffractogram of the sample that is characteristic of a crystalline drug substance.

Representative XRPD peaks of Compound I-2 • HCl • H ² O

continuation

Thermal analysis of Compound I-2 • HCl • H? O

Thermogravimetric analysis (TGA) for Compound I-2 • HCl • H ² O was performed on TGA model Q5000 from TA Instruments. Compound I-2 • HCl • H ² O was placed in a platinum sample container and heated at 10 ° C / min at 400 ° C from room temperature. The thermogram (Figure 2d) demonstrates a 2.9% weight loss from room temperature at 100 ° C, and a 0.6% weight loss from 100 ° C to 222 ° C, which is consistent with the theoretical monohydrate (3.5%).

Differential scanning calorimetry of Compound I-2 • HCl • H? O

A DSC thermogram for Compound I-2 • HCl • H ² O was obtained using DSC Q2000 from TA Instruments. Compound I-2 • HCl • H ² O was heated at 2 ° C / min at 275 ° C from -20 ° C, and modulated at ± 1 ° C every 60 sec. The DSC thermogram (Figure 3d) reveals an endothermic peak below 200 ° C, which could correspond to the loss of 1 equivalent of HCl. Melting / recrystallization occurs between 215-245 ° C, followed by degradation.

Example 14: Compound I-2 • HCl • 2 H ² O

Compound I-2 • HCh ² H ² O can be formed from Compound I-2 • 2 HCl. (E29244-17) A suspension of Compound I-2 • 2 HCl (10.0 g, 18.6 mmol) in isopropyl alcohol (40 mL) and water (10 mL) was heated at 50 ° C for about 1 hr and then cooled below 10 ° C. The solid was collected by filtration. The filter cake was washed with 80/20 isopropyl alcohol / water (2 x 10 mL) and air dried to provide Compound I-2 • HCh ² H ² O as a yellow powder.

XRPD of Compound I-2 • HCl • ² H ² O

X-ray powder diffraction measurements were made using a PANalytical Pro-X-pert diffractometer at room temperature with copper radiation (1.54060 ° A). The incident beam optics was composed of a variable divergence slot to ensure a constant illuminated length on the sample and on the side of the diffracted beam, a fast linear solid state detector with an active length of 2.12 degrees 2 theta was used measured in a scan mode. The powder sample was packed in the indented area of a zero-bottom silicon holder and rotated for better statistics. A symmetrical scan of 4-40 degrees 2 theta was measured with a stage size of 0.017 degrees and a scan stage time of 15.5 s.

Figure 1d shows the X-ray powder diffractogram of the sample that is characteristic of a crystalline drug substance.

Representative XRPD peaks of Compound I-2 • HCl • ² H ² O

continuation

Thermal analysis of Compound I-2 • HCl • 2H? O

Thermal graphs of TGA (thermogravimetric analysis) using a TA instrument TGA Q500 respectively at a scanning speed of 10 ° C / min over a temperature range of 25-300 ° C. For TGA analysis, samples were placed in an open container. The thermogram demonstrates a weight loss of ~ 6 from room temperature at 100 ° C, which is consistent with the theoretical dihydrate (6.7%).

Differential scanning calorimetry of Compound I-2 • HCl • 2H? O

DSC (Differential Scanning Calorimetry) thermal graphs were obtained using DSC Q2000 from TA instruments at a scanning rate of 10 ° C / min over a temperature range of 25-300 ° C. For DSC analysis, samples were weighed into T-zero aluminum airtight containers that were sealed and drilled with a single hole. The DSC thermogram reveals dehydration between room temperature and 120 ° C, followed by melting / recrystallization between 170-250 ° C.

Crystal structure of Compound I-2 • HCl with water

180 mg of Compound I-2 • HCl were added to a vial with 0.8 ml of 2-propanol and 0.2 ml of water. The sealed vial was kept in an oven at 70 ° C for two weeks. Diffraction grade crystals were observed.

A yellow needle-shaped crystal with dimensions of 0.15 x 0.02 x 0.02 mm3 was selected, mounted on a MicroMount and focused on a Bruker APEX II diffractometer (V011510). Then a Kapton tube with water inside it covered the pin. The tube was sealed tightly to ensure that the crystal equilibrated with water for two days prior to diffraction experiments. Three batches of 40 separate frames were obtained in reciprocal space to provide an orientation matrix and initial cell parameters. Final cellular parameters were collected and refinement completed based on the complete data set.

A reciprocal space diffraction dataset was obtained at an angle resolution of 106 ° 28 using 0.5 ° steps with exposure times of 20 s for each frame for low angle frames and 60 s for each frame for frames high angle. The data was collected at room temperature. Integration of intensities and refinement of cellular parameters were performed using APEXII software.

CRYSTALLINE DATA

Example 15: ATR inhibition cell assay:

The compounds can be screened for their ability to inhibit intracellular ATR using an immunofluorescence microscopy assay to detect phosphorylation of the ATR histone H2AX substrate in cells treated with hydroxyurea. HT29 cells at 14,000 cells per well are plated on 96-well black imaging plates (BD 353219) in McCoy's 5A medium (Sigma M8403) supplemented with 10% fetal bovine serum (JRH Biosciences 12003), solution. dilute 1: 100 penicillin / streptomycin (Sigma P7539) and 2mM L-glutamine (Sigma G7513), and allow to adhere overnight at 37 ° C in 5% CO ² . The compounds are then added to the cell medium from a final concentration of 25 pM in serial dilutions of factor 3, and the cells are incubated at 37 ° C in 5% CO ² . After 15 min, hydroxyurea (Sigma H8627) is added to a final concentration of 2mM.

After 45 min of hydroxyurea treatment, cells are washed in PBS, fixed for 10 min in 4% formaldehyde diluted in PBS (Polysciences Inc 18814), washed in 0.2% Tween-20 in PBS (buffer wash) and permeabilize for 10 min in 0.5% Triton X-100 in PBS, all at room temperature. The cells are then washed once in wash buffer and blocked for 30 min at room temperature in 10% goat serum (Sigma G9023) diluted in wash buffer (blocking buffer). To detect H2AX phosphorylation levels, cells are then incubated for 1 hr at room temperature with a primary antibody (phosphorylated H2AX Ser139 mouse monoclonal antibody; Upstate 05-636) diluted 1: 250 in blocking buffer. The cells are then washed five times in wash buffer before incubation for 1 hr at room temperature in the dark in a mixture of secondary antibody (Alexa Fluor 488-conjugated goat anti-mouse antibody; Invitrogen A11029) and Hoechst staining (Invitrogen h 3570); diluted 1: 500 and 1: 5000, respectively, in wash buffer. The cells are then washed five times in wash buffer and, finally, 100 ul of PBS is added to each well prior to imaging.

Cell images for the intensity of Alexa Fluor 488 and Hoechst are obtained using the BD Pathway 855 Bioimager and the Attovision software (BD Biosciences, Version 1.6 / 855), to quantify phosphorylated H2AX Ser139 and DNA staining, respectively . The percentage of phosphorylated H2AX-positive nuclei is then calculated for each well in a 9-image mount at 20x magnification, using the BD Image Data Explorer (BD Biosciences Version 2.2.15) software. Phosphorylated H2AX-positive nuclei are defined as Hoechst-positive regions of interest containing an intensity of Alexa Fluor 488 at 1.75 times the average intensity of Alexa Fluor 488 in non-hydroxyurea-treated cells. The percentage of H2AX positive nuclei is finally plotted against the concentration of each compound and IC50s for intracellular ATR inhibition are determined using the Prism software (GraphPad Prism version 3.0cx for Macintosh, GraphPad software, San Diego, California , USA).

The compounds described herein can also be analyzed according to other methods known in the art (see Sarkaria et al, "Inhibition of ATM and ATR Kinase Activities by the Radiosensitizing Agent, Caffeine: Cancer Research 59: 4375-5382 (1999 ); Hickson et al, "Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM" Cancer Research 64: 9152-9159 (2004); Kim et al, "Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members "The Journal of Biological Chemistry, 274 (53): 37538-37543 (1999); and Chiang et al, " Determination of the catalytic activities of mTOR and other members of the phosphoinositide-3-kinase-related kinase family " Methods Mol. Biol.

281: 125-41 (2004)).

Example 16: ATR inhibition assay:

The compounds can be screened for their ability to inhibit ATR kinase using a radioactive phosphate incorporation assay. The tests are carried out in a mixture of 50 mM Tris / HCl (pH 7.5), 10 mM MgCl ² and 1 mM DTT. Final substrate concentrations are 10 pM [y-33P] ATP (3mCi from 33P ATP / mmol ATP, Perkin Elmer) and 800 pM target peptide (ASELPASQPQPFSAKKK).

The tests are carried out at 25 ° C in the presence of 5 nM full length ATR. A test buffer stock solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 13.5 µl of the stock solution is placed in a 96-well plate followed by the addition of 2 µl of serial dilutions of the test compound, containing DMSO stock solution (normally starting from a final concentration of 15 pM with serial dilutions factor 3), in duplicate (final DMSO concentration of 7%). The plate is preincubated for 10 minutes at 25 ° C and the reaction by adding 15 | jl of [y-33P] ATP (final concentration 10 ^{| j} M).

The reaction is stopped after 24 hours by adding 30 µl of 0.1M phosphoric acid containing 2mM ATP. A 96-well multi-scan phosphocellulose filter plate (Millipore, Cat. No. MAPHN0B50) is pretreated with 100 µl of 0.2M phosphoric acid prior to the addition of 45 µl of the assay stop mix. The plate is washed with 5 x 200 jl of 0.2 M phosphoric acid. After drying, 100 jl of Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) are added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing the average background values from all data points, the Ki (ap) data is calculated from the non-linear regression analysis of the initial constant data using the dPrism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad software, San Diego, California, USA).

In general, the compounds of the present invention are effective in inhibiting ATR. Compounds I-1, I-2, II-1, II-2, II-3 and II-4 inhibit ATR at Ki values below 0.001 jM.

Example 17: Cisplatin Sensitization Assay

The compounds can be screened for their ability to sensitize HCT116 colorectal cancer cells to cisplatin using a 96 hr Cell Viability Assay (MTS). HCT116 cells, which possess an ATM signaling defect for cisplatin (see, Kim et al .; Oncogene 21: 3864 (2002); see also, Takemura et al .; JBC 281: 30814 (2006)) are seeded plated at 470 cells per well in 96-well polystyrene plates (Costar 3596), in 150 jl of McCoy's 5A medium (Sigma M8403) supplemented with 10% fetal bovine serum (JRH Biosciences 12003), penicillin / streptomycin solution diluted 1: 100 (Sigma P7539) and 2mM L-glutamine (Sigma G7513), and allowed to adhere overnight at 37 ° C in 5% CO ² . The compounds and cisplatin are then added simultaneously to the cell medium, in serial dilutions with factor 2 from a final concentration greater than 10 jM as a complete matrix of concentrations in a final cell volume of 200 jl, and the cells are incubated then at 37 ° C in 5% CO ² . After 96 hr, 40 µl of MTS reagent (Promega G358a) is added to each well and the cells are incubated for 1 hr at 37 ° C in 5% CO ² . Finally, absorbance at 490 nm is measured using a SpectraMax Plus 384 reader (Molecular Devices) and the concentration of compound required to reduce the IC50 of cisplatin alone is reported by at least 3-fold (up to 1 decimal).

Example 18: Single agent activity for HCT116

The compounds can be screened for their activity as unique agents against HCT116 colorectal cancer cells, using a 96 hr cell viability assay (MTS). HCT116 is plated at 470 cells per well in 96-well polystyrene plates (Costar 3596), in 150 ml of McCoy's 5A medium (Sigma M8403) supplemented with 10% fetal bovine serum (JRH Biosciences 12003), 1: 100 dilute penicillin / streptomycin solution (Sigma P7539) and 2mM L-glutamine (Sigma G7513), and allowed to adhere overnight at 37 ° C in 5% CO ² . The compounds are then added to the cell medium, in serial dilutions with factor 2 from a final concentration greater than 10 jM as a complete matrix of concentrations in a final cell volume of 200 jl, and the cells are then incubated at 37 ° C in CO ² at 5%. After 96 hr, 40 µl of MTS reagent (Promega G358a) is added to each well and the cells are incubated for 1 hr at 37 ° C in 5% CO ² . Finally, absorbance at 490 nm is measured using a SpectraMax Plus 384 reader (Molecular Devices) and IC50 values can be calculated.

Data for Examples 18-21

Claims (20)

1. A process to prepare a compound of formula I-2 :

or a salt thereof, comprising the step of reacting a compound of formula 4-iv :

with a compound of the following structure:

under suitable coupling conditions to form a compound of formula 5-i :

wherein suitable cross coupling conditions comprise combining a suitable palladium catalyst with a suitable base in a suitable solvent, and wherein the suitable palladium catalyst is selected from Pd [P (tBu) ³ ] ² , Pd (dtbpf) Cl ² , Pd (PPh ³ ) ² Cl ² , Pd (PCy ³ ) ² Cl ² , Pd (dppf) Cl ² and Pd (dppe) Cl ² ; the suitable solvent is selected from one or more of the following: toluene, MeCN, water, EtOH, iPA, 2-Me-THF or IPAc; and the suitable base is selected from K ² CO ³ , Na ² CO ³ or K ³ PO ⁴ . 2. The process of claim 1, further comprising a step of preparing the compound of formula 4-iv :

by reacting a compound of formula 4-iii :

with a compound of formula 4-ii :

under suitable cycloaddition conditions. 3. The process of claim 2, wherein the suitable cycloaddition conditions comprise a suitable base selected from pyridine, DIEA, TEA, t-BuONa or K ² CO ³ and a suitable solvent selected from acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran , MTBE, EtOAc, i-PrOAc, DCM, toluene, DMF and methanol. 4. The process of claim 2, further comprising a step of preparing the compound of formula 4-ii:

by reacting a compound of formula 4-i :

under suitable chloroxime formation conditions. 5. The process of claim 4, wherein the suitable chloroxime formation conditions comprise adding HCl in dioxane to a solution of a compound of formula 4-i in the presence of NCS, in a suitable solvent selected from non-protic solvents, aromatic hydrocarbons and alkyl acetates. 6. The process of claim 5, wherein the solvent is a non-protic solvent selected from DCM, DCE, THF and dioxane. 7. The process of claim 5, wherein the solvent is an aromatic hydrocarbon selected from toluene and xylenes. 8. The process of claim 5, wherein the solvent is an alkyl acetate selected from isopropyl acetate and ethyl acetate. 9. The process of claim 4, further comprising a step of preparing the compound of formula 4-i :

by reacting a compound of formula 3b:

under suitable oxime formation conditions. The process of claim 9, wherein the suitable oxime formation conditions consist of a single stage sequence or a two stage sequence. 11. The process of claim 10, wherein the suitable oxime formation conditions comprise a single step sequence comprising treating the compound of formula 3b with NH ² OH-HCl in a mixture of THF and water. 12. The process of claim 11, wherein 1 equivalent of the compound of formula 3b is combined with 1.1 equivalents of NH ² OH-HCl in a 10: 1 v / v mixture of THF / water. 13. The process of claim 10, wherein the suitable oxime formation conditions comprise a two-step sequence, wherein the two-step sequence comprises a first step of deprotecting the ketal group in the compound of formula 3b :

under suitable deprotection conditions to provide the corresponding aldehyde, and a second step of subjecting the corresponding aldehyde to suitable oxime formation conditions. 14. The process of claim 9, further comprising a step of preparing the compound of formula 3b : by reacting a compound of formula 2b:

in conditions of protection with suitable Boc. 15. The process of claim 14, further comprising a step of preparing the compound of formula 2b :

by reacting a compound of formula 1b :

with methylamine under suitable reductive amination conditions. 16. The process of claim 15, wherein the suitable reducing amination conditions comprise adding a reducing agent selected from NaBH ⁴ NaBH ⁴ , NaBHaCN and NaBH (OAc ^{) 3} in the presence of a solvent selected from dichloromethane (DCM), dichloroethane (DCE), methanol, ethanol, 1-propanol and isopropanol, dioxane, tetrahydrofuran and 2-methyltetrahydrofuran. 17. The process of claim 16, wherein the suitable reductive amination conditions further comprise a base selected from triethylamine and diisopropylethylamine. 18. The process of claim 17, wherein suitable reductive amination conditions comprise adding 1.2 equivalents of NaBH ⁴ capsules in the presence of trimethylamine in methanol. 19. The process of claim 1, wherein the suitable Boc deprotection conditions comprise adding a suitable Boc deprotection agent selected from TMS-Cl, HCl, TBAF, H ³ PO ⁴ or TFA and the suitable solvent is selected between acetone, toluene, methanol, ethanol, 1-propanol, isopropanol, CH ² O ² , EtOAc, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or diethyl ether. 20. The process of claim 19, wherein the suitable Boc deprotecting agent is HCl or TFA and the suitable solvent is acetone or CH ² Cl ² .